Parkinson's disease has long been considered a disorder that primarily affects the brain,as it is defined by the dopaminergic neurodegeneration in the substantia nigra and the brain accumulation of Lewy bodies con...Parkinson's disease has long been considered a disorder that primarily affects the brain,as it is defined by the dopaminergic neurodegeneration in the substantia nigra and the brain accumulation of Lewy bodies containingα-synuclein protein.In recent decades,however,accumulating research has revealed that Parkinson's disease also involves the gut and uncovered an intimate and important bidirectional link between the brain and the gut,called the“gut–brain axis.”Numerous clinical studies demonstrate that gut dysfunction frequently precedes motor symptoms in Parkinson's disease patients,with findings including impaired intestinal permeability,heightened inflammation,and distinct gut microbiome profiles and metabolites.Furthermore,α-synuclein deposition has been consistently observed in the gut of Parkinson's disease patients,suggesting a potential role in disease initiation.Importantly,individuals with vagotomy have a reduced Parkinson's disease risk.From these observations,researchers have hypothesized thatα-synuclein accumulation may initiate in the gut and subsequently propagate to the central dopaminergic neurons through the gut–brain axis,leading to Parkinson's disease.This review comprehensively examines the gut's involvement in Parkinson's disease,focusing on the concept of a gut-origin for the disease.We also examine the interplay between altered gut-related factors and the accumulation of pathologicalα-synuclein in the gut of Parkinson's disease patients.Given the accessibility of the gut to both dietary and pharmacological interventions,targeting gut-localizedα-synuclein represents a promising avenue for developing effective Parkinson's disease therapies.展开更多
High-mobility group box 1 was first discovered in the calf thymus as a DNA-binding nuclear protein and has been widely studied in diverse fields,including neurology and neuroscience.High-mobility group box 1 in the ex...High-mobility group box 1 was first discovered in the calf thymus as a DNA-binding nuclear protein and has been widely studied in diverse fields,including neurology and neuroscience.High-mobility group box 1 in the extracellular space functions as a pro-inflammatory damage-associated molecular pattern,which has been proven to play an important role in a wide variety of central nervous system disorders such as ischemic stroke,Alzheimer’s disease,frontotemporal dementia,Parkinson’s disease,multiple sclerosis,epilepsy,and traumatic brain injury.Several drugs that inhibit high-mobility group box 1 as a damage-associated molecular pattern,such as glycyrrhizin,ethyl pyruvate,and neutralizing anti-high-mobility group box 1 antibodies,are commonly used to target high-mobility group box 1 activity in central nervous system disorders.Although it is commonly known for its detrimental inflammatory effect,high-mobility group box 1 has also been shown to have beneficial pro-regenerative roles in central nervous system disorders.In this narrative review,we provide a brief summary of the history of high-mobility group box 1 research and its characterization as a damage-associated molecular pattern,its downstream receptors,and intracellular signaling pathways,how high-mobility group box 1 exerts the repair-favoring roles in general and in the central nervous system,and clues on how to differentiate the pro-regenerative from the pro-inflammatory role.Research targeting high-mobility group box 1 in the central nervous system may benefit from differentiating between the two functions rather than overall suppression of high-mobility group box 1.展开更多
Elucidating the complex dynamic cellular organization in the hypothalamus is critical for understanding its role in coordinating fundamental body functions. Over the past decade, single-cell and spatial omics technolo...Elucidating the complex dynamic cellular organization in the hypothalamus is critical for understanding its role in coordinating fundamental body functions. Over the past decade, single-cell and spatial omics technologies have significantly evolved, overcoming initial technical challenges in capturing and analyzing individual cells. These high-throughput omics technologies now offer a remarkable opportunity to comprehend the complex spatiotemporal patterns of transcriptional diversity and cell-type characteristics across the entire hypothalamus. Current single-cell and single-nucleus RNA sequencing methods comprehensively quantify gene expression by exploring distinct phenotypes across various subregions of the hypothalamus. However, single-cell/single-nucleus RNA sequencing requires isolating the cell/nuclei from the tissue, potentially resulting in the loss of spatial information concerning neuronal networks. Spatial transcriptomics methods, by bypassing the cell dissociation, can elucidate the intricate spatial organization of neural networks through their imaging and sequencing technologies. In this review, we highlight the applicative value of single-cell and spatial transcriptomics in exploring the complex molecular-genetic diversity of hypothalamic cell types, driven by recent high-throughput achievements.展开更多
Spinal cord injury results in permanent loss of neurological functions due to severance of neural networks.Transplantation of neural stem cells holds promise to repair disrupted connections.Yet,ensuring the survival a...Spinal cord injury results in permanent loss of neurological functions due to severance of neural networks.Transplantation of neural stem cells holds promise to repair disrupted connections.Yet,ensuring the survival and integration of neural stem cells into the host neural circuit remains a formidable challenge.Here,we investigated whether modifying the intrinsic properties of neural stem cells could enhance their integration post-transplantation.We focused on phosphatase and tensin homolog(PTEN),a well-characterized tumor suppressor known to critically regulate neuronal survival and axonal regeneration.By deleting Pten in mouse neural stem cells,we observed increased neurite outgrowth and enhanced resistance to neurotoxic environments in culture.Upon transplantation into injured spinal cords,Pten-deficient neural stem cells exhibited higher survival and more extensive rostrocaudal distribution.To examine the potential influence of partial PTEN suppression,rat neural stem cells were treated with short hairpin RNA targeting PTEN,and the PTEN knockdown resulted in significant improvements in neurite growth,survival,and neurosphere motility in vitro.Transplantation of sh PTEN-treated neural stem cells into the injured spinal cord also led to an increase in graft survival and migration to an extent similar to that of complete deletion.Moreover,PTEN suppression facilitated neurite elongation from NSC-derived neurons migrating from the lesion epicenter.These findings suggest that modifying intrinsic signaling pathways,such as PTEN,within neural stem cells could bolster their therapeutic efficacy,offering potential avenues for future regenerative strategies for spinal cord injury.展开更多
Traumatic injuries to spinal cord elicit diverse signaling pathways leading to unselective and complex pathological outcomes：death of multiple classes of neural cells,formation of cystic cavities and glial scars,disr...Traumatic injuries to spinal cord elicit diverse signaling pathways leading to unselective and complex pathological outcomes：death of multiple classes of neural cells,formation of cystic cavities and glial scars,disruption of axonal connections,and demyelination of spared axons,all of which can contribute more or less to debilitating functional impairments found in patients with spinal cord injury.展开更多
Stress ulceration is single or multiple mucosal defects with/without bleeding from the gastric mucosa during the physiologic stress. Oxidative stress (OS) is a key pathogenic factor in psychogenic stress-induced acute...Stress ulceration is single or multiple mucosal defects with/without bleeding from the gastric mucosa during the physiologic stress. Oxidative stress (OS) is a key pathogenic factor in psychogenic stress-induced acute gastric mucosal lesion (AGML). Fermented papaya preparation (FPP) is reported to have oxygen radical scavenging activity and is effective in OS-related diseases. Here, we investigated the protective effects and the mechanism of action of FPP on stress-induced AGML in rats, induced by water immersion restraint stress (WIRS). Exposure of rats to 6-hour WIRS resulted in the appearance of splinter hemorrhages and mucosal lesions in the stomach. WIRS induced significant increase in lipid peroxidation and decrease in superoxide dismutase-like activity in both the plasma and gastric mucosa. WIRS also significantly increased myeloperoxidase activity together with Nuclear factor-kappaB (NF-kB) activation in gastric mucosa. FPP reduced all the above changes. The results suggest that oral administration of FPP provides protection against WIRS-induced acute gastric mucosal lesions through its anti-oxidative and anti-inflammatory properties.展开更多
The interesting task here is to study the frequency-current(f–I)curve and phase response curve(PRC),subject to neural temperature variations,because the f–I curve and PRC are important measurements to understand dyn...The interesting task here is to study the frequency-current(f–I)curve and phase response curve(PRC),subject to neural temperature variations,because the f–I curve and PRC are important measurements to understand dynamical mechanisms of generation of neural oscillations,and the neural temperature is widely known to significantly affect the oscillations.Nevertheless,little is discussed about how the temperature affects the f–I curve and PRC.In this study,frequencies of the neural oscillations,modulated with the temperature variations,are quantified with an average of the PRC.The frequency gradient with respect to temperature derived here gives clear classifications of the PRC,regardless of the form.It is also indicated that frequency decreases with an increase in temperature,resulted from bifurcation switching of the saddle-homoclinic to the saddle-node on an invariant circle.展开更多
We have shown previously that chronic administration of adrenocorticotropic hormone (ACTH) causes a significant decrease in hippocampal cell proliferation and neurogenesis. This effect in rats treated chronically with...We have shown previously that chronic administration of adrenocorticotropic hormone (ACTH) causes a significant decrease in hippocampal cell proliferation and neurogenesis. This effect in rats treated chronically with ACTH was not influenced by the chronic administration of imipramine, but was reversed by coadministration of imipramine and lithium. The present study was undertaken to further characterize the mechanism underlying the effect of imipramine and lithium on hippocampal cell proliferation and neurogenesis, by investigating the effects of treatment on the expression of brain-derived neurotrophic factor (BDNF), total cyclic adenosine monophosphate response element-binding protein (CREB), and phosphorylated CREB (pCREB) of the CREB signaling system, as well as Wnt 3a and cyclin D1 of the Wnt signaling pathway in the hippocampus of saline- and ACTH-treated rats. ACTH treatment significantly decreased the expression of cyclin D1. Treatment with imipramine and lithium increased the expression of cyclin D1 in ACTH-treated rats. However, the expression of BDNF, CREB, pCREB, and Wnt 3a did not change in either saline-treated or ACTH-treated rats. These findings suggest that the antidepressant effect of imipramine and lithium in ACTH-treatment-resistant rats may be attributed, at least in part, to an enhancement of cyclin D1 expression.展开更多
It is well known that α-synuclein (αS) plays an important role in the pathogenesis of Parkinson’s disease (PD). Moreover, oxidative stress is also thought to be an important factor in PD due to induction of dopamin...It is well known that α-synuclein (αS) plays an important role in the pathogenesis of Parkinson’s disease (PD). Moreover, oxidative stress is also thought to be an important factor in PD due to induction of dopaminergic neuronal cell death by free radicals and enhancement of αS fibrillation by oxidized stress. In the present study, to clarify the role of glutathione (GSH), an intracellular antioxidant, on the molecular mechanism of αS-induced cell injury, we examined the effects of L-buthionine-SR-sulfoximine (BSO), a GSH synthase inhibitor, with or without N-acetyl-L-cysteine (NAC), a source of GSH, on αS-induced cell injury in human neuroblastoma SH-SY5Y cells. Treatment with BSO significantly reduced the cell viability of both empty-vector- and αS-transfected SH-SY5Y cells in a dose-dependent manner (p < 0.01), although the ratio of αS-induced reduction of cell viability in α-syn-transfected cells was much greater than that in empty-vector-transfected cells. Moreover, BSO significantly reduced the intracellular total GSH level in both types of transformant cells. However, NAC significantly prevented BSO-induced reduction of both cell viability and GSH level in the αS-transfected cells. These findings suggest that GSH plays an important role in αS-induced cell injury by reducing cell viability.展开更多
Non-alcoholic steatohepatitis (NASH) can progress to cirrhosis or hepatocellular carcinoma. Oxidative stress is implicated in NASH progression. Fermented papaya preparation (FPP) has oxygen radical scavenging activity...Non-alcoholic steatohepatitis (NASH) can progress to cirrhosis or hepatocellular carcinoma. Oxidative stress is implicated in NASH progression. Fermented papaya preparation (FPP) has oxygen radical scavenging activity and is effective in oxidative stress-related diseases. We investigated the effects of FPP on NASH progression using a rat NASH model. Plasma biochemical parameters and lipid peroxidation in the liver were elevated in NASH rats. Histologically, the liver of NASH rats showed liver fibrosis, mitochondrial dysfunction and over-expression of microsomal CYP2E1. Myeloperoxidase activity and nuclear factor-kappaB activation were also markedly increased in NASH. Oral administration of FPP ameliorated these changes in NASH rats. These results suggest that FPP halts NASH progression through its anti-oxidative and antiinflammatory properties.展开更多
Zonisamide (ZNS), a commonly used anticonvulsant, scavenged hydroxyl radicals at a clinically relevant concentration. Reactants of ZNS with hydrogen peroxide and with hydrogen peroxide plus UV irradiation, yielding hy...Zonisamide (ZNS), a commonly used anticonvulsant, scavenged hydroxyl radicals at a clinically relevant concentration. Reactants of ZNS with hydrogen peroxide and with hydrogen peroxide plus UV irradiation, yielding hydroxyl radicals, were analyzed by the LC/MS technique. Many small fragments were found in the both reactions, suggesting that ZNS was decomposed not only by hydroxyl radicals but also by hydrogen peroxide. Furthermore, mass-fragment-grams showed that m/z: 213 (ZNS itself) was decreased markedly and m/z: 118 (may be a decomposed product by ring cleavage of ZNS) was detected specifically by treatment with hydroxyl radical. These data suggested that ZNS may react directly with free radicals.展开更多
Neuronal necroptosis-an emerging form of regulated cell death associated with neuroinflammatory signaling:Alzheimer’s disease(AD)is characterized by the presence of extracellular amyloid-β(Aβ)plaques and intracellu...Neuronal necroptosis-an emerging form of regulated cell death associated with neuroinflammatory signaling:Alzheimer’s disease(AD)is characterized by the presence of extracellular amyloid-β(Aβ)plaques and intracellular tau neurofibrillary tangles as well as progressive neuronal loss.Recent evidence has suggested that prolonged neuroinflammation with increased levels of cytokines,arising from neuronal injury,innate immune responses from glial cells,and peripheral inflammation,leads to neuronal death and AD progression.展开更多
A wheeled mobile mechanism with a passive and/or active linkage mechanism for rough terrain environment is developed and evaluated. The wheeled mobile mechanism which has high mobility in rough terrain needs sophistic...A wheeled mobile mechanism with a passive and/or active linkage mechanism for rough terrain environment is developed and evaluated. The wheeled mobile mechanism which has high mobility in rough terrain needs sophisticated system to adapt various environments. We focus on the development of a switching controller system for wheeled mobile robots in rough terrain. This system consists of two sub-systems： an environment recognition system using link angles and an adaptive control system. In the environment recognition system, we introduce a Self-Organizing Map （SOM） for clustering link angles. In the adaptive controllers, we introduce neural networks to calculate the inverse model of the wheeled mobile robot. The environment recognition system can recognize the environment in which the robot travels, and the adjustable controllers are tuned by experimental results for each environment. The dual sub-system switching controller system is experimentally evaluated. The system recognizes its environment and adapts by switching the adjustable controllers. This system demonstrates superior performance to a well-tuned single PID controller.展开更多
Subcortical ischemic white matter injury(SIWMI),pathological correlate of white matter hyperintensities or leukoaraiosis on magnetic resonance imaging,is a common cause of cognitive decline in elderly.Despite its high...Subcortical ischemic white matter injury(SIWMI),pathological correlate of white matter hyperintensities or leukoaraiosis on magnetic resonance imaging,is a common cause of cognitive decline in elderly.Despite its high prevalence,it remains unknown how various components of the white matter degenerate in response to chronic ischemia.This incomplete knowledge is in part due to a lack of adequate animal model.The current review introduces various SIWMI animal models and aims to scrutinize their advantages and disadvantages primarily in regard to the pathological manifestations of white matter components.The SIWMI animal models are categorized into 1)chemically induced SIWMI models,2)vascular occlusive SIWMI models,and 3)SIWMI models with comorbid vascular risk factors.Chemically induced models display consistent lesions in predetermined areas of the white matter,but the abrupt evolution of lesions does not appropriately reflect the progressive pathological processes in human white matter hyperintensities.Vascular occlusive SIWMI models often do not exhibit white matter lesions that are sufficiently unequivocal to be quantified.When combined with comorbid vascular risk factors(specifically hypertension),however,they can produce progressive and definitive white matter lesions including diffuse rarefaction,demyelination,loss of oligodendrocytes,and glial activation,which are by far the closest to those found in human white matter hyperintensities lesions.However,considerable surgical mortality and unpredictable natural deaths during a follow-up period would necessitate further refinements in these models.In the meantime,in vitro SIWMI models that recapitulate myelinated white matter track may be utilized to study molecular mechanisms of the ischemic white matter injury.Appropriate in vivo and in vitro SIWMI models will contribute in a complementary manner to making a breakthrough in developing effective treatment to prevent progression of white matter hyperintensities.展开更多
Axons in central nervous system （CNS） do not regenerate spontaneously after injuries such as stroke and traumatic spinal cord iniury. Both intrinsic and extrinsic factors are responsible for the regeneration fail- u...Axons in central nervous system （CNS） do not regenerate spontaneously after injuries such as stroke and traumatic spinal cord iniury. Both intrinsic and extrinsic factors are responsible for the regeneration fail- ure, Although intensive research efforts have been invested on extrinsic regeneration inhibitors, the extent to which glial inhibitors contribute to the regeneration failure in viva still remains elusive. Recent exper- imental evidence has rekindled interests in intrinsic factors for the regulation of regeneration capacity in adult mammals. In this review, we propose that activating macrophages with pro-regenerative molecular signatures could be a novel approach for boosting intrinsic regenerative capacity of CNS neurons. Using a conditioning injury model in which regeneration of central branches of dorsal root ganglia sensory neu- rons is enhanced by a preceding injury to the peripheral branches, we have demonstrated that perineuronal macrophages surrounding dorsal root ganglia neurons are critically involved in the maintenance of en- hanced regeneration capacity. Neuron-derived chemokine （C-C motif） ligand 2 （CCL2） seems to mediate neuron-macrophage interactions conveying injury signals to perineuronal macrophages taking on a soley pro-regenerative phenotype, which we designate as regeneration-associated macrophages （RAMs）. Ma- nipulation of the CCL2 signaling could boost regeneration potential mimicking the conditioning injury, suggesting that the chemokine-mediated RAM activation could be utilized as a regenerative therapeutic strategy for CNS injuries.展开更多
Details about the structure of a network model are revealed at the spontaneous spike activity level,in which the power-law of synchrony is optimized to that observed in the CA3 hippocampal slice cultures.The network m...Details about the structure of a network model are revealed at the spontaneous spike activity level,in which the power-law of synchrony is optimized to that observed in the CA3 hippocampal slice cultures.The network model is subject to spike noise with exponentially distributed interspike intervals.The excitatory(E)and/or inhibitory(I)neurons interact through synapses whose weights show a log-normal distribution.The spike behavior observed in the network model with the appropriate log-normal distributed synaptic weights fits best to that observed in the experiment.The best-fit is then achieved with high activities of I neurons having a hub-like structure,in which the I neurons,subject to optimized spike noise,are intensively projected from low active E neurons.展开更多
Background Artificial intelligence(AI)has rapidly permeated various sectors,including healthcare,highlighting its potential to facilitate mental health assessments.This study explores the underexplored domain of AI’s...Background Artificial intelligence(AI)has rapidly permeated various sectors,including healthcare,highlighting its potential to facilitate mental health assessments.This study explores the underexplored domain of AI’s role in evaluating prognosis and long-term outcomes in depressive disorders,offering insights into how AI large language models(LLMs)compare with human perspectives.Methods Using case vignettes,we conducted a comparative analysis involving different LLMs(ChatGPT-3.5,ChatGPT-4,Claude and Bard),mental health professionals(general practitioners,psychiatrists,clinical psychologists and mental health nurses),and the general public that reported previously.We evaluate the LLMs ability to generate prognosis,anticipated outcomes with and without professional intervention,and envisioned long-term positive and negative consequences for individuals with depression.Results In most of the examined cases,the four LLMs consistently identified depression as the primary diagnosis and recommended a combined treatment of psychotherapy and antidepressant medication.ChatGPT-3.5 exhibited a significantly pessimistic prognosis distinct from other LLMs,professionals and the public.ChatGPT-4,Claude and Bard aligned closely with mental health professionals and the general public perspectives,all of whom anticipated no improvement or worsening without professional help.Regarding long-term outcomes,ChatGPT 3.5,Claude and Bard consistently projected significantly fewer negative long-term consequences of treatment than ChatGPT-4.Conclusions This study underscores the potential of AI to complement the expertise of mental health professionals and promote a collaborative paradigm in mental healthcare.The observation that three of the four LLMs closely mirrored the anticipations of mental health experts in scenarios involving treatment underscores the technology’s prospective value in offering professional clinical forecasts.The pessimistic outlook presented by ChatGPT 3.5 is concerning,as it could potentially diminish patients’drive to initiate or continue depression therapy.In summary,although LLMs show potential in enhancing healthcare services,their utilisation requires thorough verification and a seamless integration with human judgement and skills.展开更多
We study specific changes in repetitive firing in the two-dimensional Hindmarsh-Rose （2dHR） oscillatory sys- tem that undergoes a bifurcation transition from the supercritical Andronov-Hopf （All） type to the subcr...We study specific changes in repetitive firing in the two-dimensional Hindmarsh-Rose （2dHR） oscillatory sys- tem that undergoes a bifurcation transition from the supercritical Andronov-Hopf （All） type to the subcritical Andronov-Hopf （SAH） type. We identify dynamical mechanisms which are responsible for changes of the repeti- tive firing rate during the AH to SAH bifurcation transitions. These include frequency-shift functions in response to small perturbations of a timescale parameter, its multiplicative parameter, and an external input current in the 2dHR oscillatory system. The frequency-shift functions are explicitly represented as functions relating to the phase response curves （PRCs）. Then, we demonstrate that when the timescale is normal and relatively fast, the repetitive firing rate slightly increases and decreases respectively during the AH to SAH bifurcation transition with a change of the intrinsic parameter, whereas it decreases during the SAH to AH bifurcation transition with an increase in the timescale. By analyzing the three different frequency-shift functions, we show that such changes of the repetitive firing rate depend largely on changes of the PRC size. The PRC size for the SAH bifurcation shrinks to the PRC size for the AH bifurcation.展开更多
Large populations with multi-modal biomedical phenotypes are crucial for investigating the potential causes of human diseases.In particular,large population-based imaging studies can provide detailed imaging-derived p...Large populations with multi-modal biomedical phenotypes are crucial for investigating the potential causes of human diseases.In particular,large population-based imaging studies can provide detailed imaging-derived phenotypes(IDPs)to quantitatively describe the anatomical structure and function for assessing their associations with genetics,life-style factors and disease outcomes.However,it is not a trivial task to initiate a large population-based imaging study,considering the challenges of logistics,cost,standardisation of the image acquisition protocol,robust image analysis pipelines for IDP extraction and quality control etc.Published in Phenomics,Wang et al.describe the brain image acquisition and phenotyping protocol for the China Phenobank Project(CHPP)(Wang et al.2023),an effort to assess and understand the current health status of a Chinese population,as well as to investigate the causes and progression of common diseases in China.展开更多
Currently,standard protocols for body imaging and corresponding image processing pipelines in population-based cohort studies are unavailable,limiting the applications of body imaging.Based on the China Phenobank Proj...Currently,standard protocols for body imaging and corresponding image processing pipelines in population-based cohort studies are unavailable,limiting the applications of body imaging.Based on the China Phenobank Project(CHPP),the present study described a body imaging protocol for multiple organs,including cardiac structures,liver,spleen,pancreas,kidneys,lung,prostate,and uterus,and the corresponding image processing pipelines promoted its development.Briefly,the body imaging protocol comprised a 40-min cardiac magnetic resonance imaging(MRI)scan,a 5-min computed tomography(CT)scan,a 20-min abdominal MRI scan,and a 10-min pelvic MRI scan.The recommended image processing pipeline utilized deep learning segmentation models to facilitate the analysis of large amount of data.This study aimed to provide a reference for planning studies based on the CHPP platform.展开更多
基金supported by the National Research Foundation(NRF)of Korea(2022R1C1C1005741 and RS-2023-00217595)。
文摘Parkinson's disease has long been considered a disorder that primarily affects the brain,as it is defined by the dopaminergic neurodegeneration in the substantia nigra and the brain accumulation of Lewy bodies containingα-synuclein protein.In recent decades,however,accumulating research has revealed that Parkinson's disease also involves the gut and uncovered an intimate and important bidirectional link between the brain and the gut,called the“gut–brain axis.”Numerous clinical studies demonstrate that gut dysfunction frequently precedes motor symptoms in Parkinson's disease patients,with findings including impaired intestinal permeability,heightened inflammation,and distinct gut microbiome profiles and metabolites.Furthermore,α-synuclein deposition has been consistently observed in the gut of Parkinson's disease patients,suggesting a potential role in disease initiation.Importantly,individuals with vagotomy have a reduced Parkinson's disease risk.From these observations,researchers have hypothesized thatα-synuclein accumulation may initiate in the gut and subsequently propagate to the central dopaminergic neurons through the gut–brain axis,leading to Parkinson's disease.This review comprehensively examines the gut's involvement in Parkinson's disease,focusing on the concept of a gut-origin for the disease.We also examine the interplay between altered gut-related factors and the accumulation of pathologicalα-synuclein in the gut of Parkinson's disease patients.Given the accessibility of the gut to both dietary and pharmacological interventions,targeting gut-localizedα-synuclein represents a promising avenue for developing effective Parkinson's disease therapies.
基金supported by a grant of the M.D.-Ph.D./Medical Scientist Training Program through the Korea Health Industry Development Institute(KHIDI)funded by the Ministry of Health&Welfare,Republic of Korea(to HK)+3 种基金supported by National Research Foundation of Korea(NRF)grants funded by the Korean government(MSITMinistry of Science and ICT)(NRF2019R1A5A2026045 and NRF-2021R1F1A1061819)a grant from the Korean Health Technology R&D Project through the Korea Health Industry Development Institute(KHIDI),funded by the Ministry of Health&Welfare,Republic of Korea(HR21C1003)New Faculty Research Fund of Ajou University School of Medicine(to JYC)。
文摘High-mobility group box 1 was first discovered in the calf thymus as a DNA-binding nuclear protein and has been widely studied in diverse fields,including neurology and neuroscience.High-mobility group box 1 in the extracellular space functions as a pro-inflammatory damage-associated molecular pattern,which has been proven to play an important role in a wide variety of central nervous system disorders such as ischemic stroke,Alzheimer’s disease,frontotemporal dementia,Parkinson’s disease,multiple sclerosis,epilepsy,and traumatic brain injury.Several drugs that inhibit high-mobility group box 1 as a damage-associated molecular pattern,such as glycyrrhizin,ethyl pyruvate,and neutralizing anti-high-mobility group box 1 antibodies,are commonly used to target high-mobility group box 1 activity in central nervous system disorders.Although it is commonly known for its detrimental inflammatory effect,high-mobility group box 1 has also been shown to have beneficial pro-regenerative roles in central nervous system disorders.In this narrative review,we provide a brief summary of the history of high-mobility group box 1 research and its characterization as a damage-associated molecular pattern,its downstream receptors,and intracellular signaling pathways,how high-mobility group box 1 exerts the repair-favoring roles in general and in the central nervous system,and clues on how to differentiate the pro-regenerative from the pro-inflammatory role.Research targeting high-mobility group box 1 in the central nervous system may benefit from differentiating between the two functions rather than overall suppression of high-mobility group box 1.
基金supported by the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI)the Ministry of Health&Welfare,Republic of Korea (HR22C1734)+2 种基金the National Research Foundation (NRF) of Korea (2020R1A6A1A03043539,2020M3A9D8037604,2022R1C1C1004756)(to SBL)the NRF of Korea (2022R1C1C1005741 and RS-2023-00217595)the new faculty research fund of Ajou University School of Medicine (to EJL)。
文摘Elucidating the complex dynamic cellular organization in the hypothalamus is critical for understanding its role in coordinating fundamental body functions. Over the past decade, single-cell and spatial omics technologies have significantly evolved, overcoming initial technical challenges in capturing and analyzing individual cells. These high-throughput omics technologies now offer a remarkable opportunity to comprehend the complex spatiotemporal patterns of transcriptional diversity and cell-type characteristics across the entire hypothalamus. Current single-cell and single-nucleus RNA sequencing methods comprehensively quantify gene expression by exploring distinct phenotypes across various subregions of the hypothalamus. However, single-cell/single-nucleus RNA sequencing requires isolating the cell/nuclei from the tissue, potentially resulting in the loss of spatial information concerning neuronal networks. Spatial transcriptomics methods, by bypassing the cell dissociation, can elucidate the intricate spatial organization of neural networks through their imaging and sequencing technologies. In this review, we highlight the applicative value of single-cell and spatial transcriptomics in exploring the complex molecular-genetic diversity of hypothalamic cell types, driven by recent high-throughput achievements.
基金supported by the National Research Foundation of Korea,Nos.2021R1A2C2006110,2021M3E5D9021364,2019R1A5A2026045(to BGK)the Korea Initiative for Fostering University of Research and Innovation(KIURI)Program of the NRF funded by the MSIT(to HK),No.NRF2021M3H1A104892211(to HSK)。
文摘Spinal cord injury results in permanent loss of neurological functions due to severance of neural networks.Transplantation of neural stem cells holds promise to repair disrupted connections.Yet,ensuring the survival and integration of neural stem cells into the host neural circuit remains a formidable challenge.Here,we investigated whether modifying the intrinsic properties of neural stem cells could enhance their integration post-transplantation.We focused on phosphatase and tensin homolog(PTEN),a well-characterized tumor suppressor known to critically regulate neuronal survival and axonal regeneration.By deleting Pten in mouse neural stem cells,we observed increased neurite outgrowth and enhanced resistance to neurotoxic environments in culture.Upon transplantation into injured spinal cords,Pten-deficient neural stem cells exhibited higher survival and more extensive rostrocaudal distribution.To examine the potential influence of partial PTEN suppression,rat neural stem cells were treated with short hairpin RNA targeting PTEN,and the PTEN knockdown resulted in significant improvements in neurite growth,survival,and neurosphere motility in vitro.Transplantation of sh PTEN-treated neural stem cells into the injured spinal cord also led to an increase in graft survival and migration to an extent similar to that of complete deletion.Moreover,PTEN suppression facilitated neurite elongation from NSC-derived neurons migrating from the lesion epicenter.These findings suggest that modifying intrinsic signaling pathways,such as PTEN,within neural stem cells could bolster their therapeutic efficacy,offering potential avenues for future regenerative strategies for spinal cord injury.
基金supported by a National Research Foundation of Korea grant funded by the Korean Government(NRF-2014R1A1A2056452 to D.H.H.and NRF-2014M3A9B6034224 to BGK)
文摘Traumatic injuries to spinal cord elicit diverse signaling pathways leading to unselective and complex pathological outcomes：death of multiple classes of neural cells,formation of cystic cavities and glial scars,disruption of axonal connections,and demyelination of spared axons,all of which can contribute more or less to debilitating functional impairments found in patients with spinal cord injury.
文摘Stress ulceration is single or multiple mucosal defects with/without bleeding from the gastric mucosa during the physiologic stress. Oxidative stress (OS) is a key pathogenic factor in psychogenic stress-induced acute gastric mucosal lesion (AGML). Fermented papaya preparation (FPP) is reported to have oxygen radical scavenging activity and is effective in OS-related diseases. Here, we investigated the protective effects and the mechanism of action of FPP on stress-induced AGML in rats, induced by water immersion restraint stress (WIRS). Exposure of rats to 6-hour WIRS resulted in the appearance of splinter hemorrhages and mucosal lesions in the stomach. WIRS induced significant increase in lipid peroxidation and decrease in superoxide dismutase-like activity in both the plasma and gastric mucosa. WIRS also significantly increased myeloperoxidase activity together with Nuclear factor-kappaB (NF-kB) activation in gastric mucosa. FPP reduced all the above changes. The results suggest that oral administration of FPP provides protection against WIRS-induced acute gastric mucosal lesions through its anti-oxidative and anti-inflammatory properties.
基金Supported by the Grant-in-Aid for Challenging Exploratory Research from MEXT(No 25540110).
文摘The interesting task here is to study the frequency-current(f–I)curve and phase response curve(PRC),subject to neural temperature variations,because the f–I curve and PRC are important measurements to understand dynamical mechanisms of generation of neural oscillations,and the neural temperature is widely known to significantly affect the oscillations.Nevertheless,little is discussed about how the temperature affects the f–I curve and PRC.In this study,frequencies of the neural oscillations,modulated with the temperature variations,are quantified with an average of the PRC.The frequency gradient with respect to temperature derived here gives clear classifications of the PRC,regardless of the form.It is also indicated that frequency decreases with an increase in temperature,resulted from bifurcation switching of the saddle-homoclinic to the saddle-node on an invariant circle.
文摘We have shown previously that chronic administration of adrenocorticotropic hormone (ACTH) causes a significant decrease in hippocampal cell proliferation and neurogenesis. This effect in rats treated chronically with ACTH was not influenced by the chronic administration of imipramine, but was reversed by coadministration of imipramine and lithium. The present study was undertaken to further characterize the mechanism underlying the effect of imipramine and lithium on hippocampal cell proliferation and neurogenesis, by investigating the effects of treatment on the expression of brain-derived neurotrophic factor (BDNF), total cyclic adenosine monophosphate response element-binding protein (CREB), and phosphorylated CREB (pCREB) of the CREB signaling system, as well as Wnt 3a and cyclin D1 of the Wnt signaling pathway in the hippocampus of saline- and ACTH-treated rats. ACTH treatment significantly decreased the expression of cyclin D1. Treatment with imipramine and lithium increased the expression of cyclin D1 in ACTH-treated rats. However, the expression of BDNF, CREB, pCREB, and Wnt 3a did not change in either saline-treated or ACTH-treated rats. These findings suggest that the antidepressant effect of imipramine and lithium in ACTH-treatment-resistant rats may be attributed, at least in part, to an enhancement of cyclin D1 expression.
文摘It is well known that α-synuclein (αS) plays an important role in the pathogenesis of Parkinson’s disease (PD). Moreover, oxidative stress is also thought to be an important factor in PD due to induction of dopaminergic neuronal cell death by free radicals and enhancement of αS fibrillation by oxidized stress. In the present study, to clarify the role of glutathione (GSH), an intracellular antioxidant, on the molecular mechanism of αS-induced cell injury, we examined the effects of L-buthionine-SR-sulfoximine (BSO), a GSH synthase inhibitor, with or without N-acetyl-L-cysteine (NAC), a source of GSH, on αS-induced cell injury in human neuroblastoma SH-SY5Y cells. Treatment with BSO significantly reduced the cell viability of both empty-vector- and αS-transfected SH-SY5Y cells in a dose-dependent manner (p < 0.01), although the ratio of αS-induced reduction of cell viability in α-syn-transfected cells was much greater than that in empty-vector-transfected cells. Moreover, BSO significantly reduced the intracellular total GSH level in both types of transformant cells. However, NAC significantly prevented BSO-induced reduction of both cell viability and GSH level in the αS-transfected cells. These findings suggest that GSH plays an important role in αS-induced cell injury by reducing cell viability.
文摘Non-alcoholic steatohepatitis (NASH) can progress to cirrhosis or hepatocellular carcinoma. Oxidative stress is implicated in NASH progression. Fermented papaya preparation (FPP) has oxygen radical scavenging activity and is effective in oxidative stress-related diseases. We investigated the effects of FPP on NASH progression using a rat NASH model. Plasma biochemical parameters and lipid peroxidation in the liver were elevated in NASH rats. Histologically, the liver of NASH rats showed liver fibrosis, mitochondrial dysfunction and over-expression of microsomal CYP2E1. Myeloperoxidase activity and nuclear factor-kappaB activation were also markedly increased in NASH. Oral administration of FPP ameliorated these changes in NASH rats. These results suggest that FPP halts NASH progression through its anti-oxidative and antiinflammatory properties.
文摘Zonisamide (ZNS), a commonly used anticonvulsant, scavenged hydroxyl radicals at a clinically relevant concentration. Reactants of ZNS with hydrogen peroxide and with hydrogen peroxide plus UV irradiation, yielding hydroxyl radicals, were analyzed by the LC/MS technique. Many small fragments were found in the both reactions, suggesting that ZNS was decomposed not only by hydroxyl radicals but also by hydrogen peroxide. Furthermore, mass-fragment-grams showed that m/z: 213 (ZNS itself) was decreased markedly and m/z: 118 (may be a decomposed product by ring cleavage of ZNS) was detected specifically by treatment with hydroxyl radical. These data suggested that ZNS may react directly with free radicals.
基金supported by a Lee Kong Chian School of Medicine Dean’s Postdoctoral Fellowship(021207-00001)from Nanyang Technological University Singaporea Mistletoe Research Fellowship(022522-00001)from the Momental Foundation USA(to CHL).
文摘Neuronal necroptosis-an emerging form of regulated cell death associated with neuroinflammatory signaling:Alzheimer’s disease(AD)is characterized by the presence of extracellular amyloid-β(Aβ)plaques and intracellular tau neurofibrillary tangles as well as progressive neuronal loss.Recent evidence has suggested that prolonged neuroinflammation with increased levels of cytokines,arising from neuronal injury,innate immune responses from glial cells,and peripheral inflammation,leads to neuronal death and AD progression.
文摘A wheeled mobile mechanism with a passive and/or active linkage mechanism for rough terrain environment is developed and evaluated. The wheeled mobile mechanism which has high mobility in rough terrain needs sophisticated system to adapt various environments. We focus on the development of a switching controller system for wheeled mobile robots in rough terrain. This system consists of two sub-systems： an environment recognition system using link angles and an adaptive control system. In the environment recognition system, we introduce a Self-Organizing Map （SOM） for clustering link angles. In the adaptive controllers, we introduce neural networks to calculate the inverse model of the wheeled mobile robot. The environment recognition system can recognize the environment in which the robot travels, and the adjustable controllers are tuned by experimental results for each environment. The dual sub-system switching controller system is experimentally evaluated. The system recognizes its environment and adapts by switching the adjustable controllers. This system demonstrates superior performance to a well-tuned single PID controller.
基金This work was supported by the National Research Foundation of Korea(NRF)grants funded by the Korea government(MSIT,Ministry of Science and ICT)(NRF-2018M3A9E8023853(to JYC)NRF-2018R1C1B6006145(to JYC)NRF-2018R1A2A1A05020292(to BGK)and NRF-2019R1A5A2026045(to JYC and BGK).
文摘Subcortical ischemic white matter injury(SIWMI),pathological correlate of white matter hyperintensities or leukoaraiosis on magnetic resonance imaging,is a common cause of cognitive decline in elderly.Despite its high prevalence,it remains unknown how various components of the white matter degenerate in response to chronic ischemia.This incomplete knowledge is in part due to a lack of adequate animal model.The current review introduces various SIWMI animal models and aims to scrutinize their advantages and disadvantages primarily in regard to the pathological manifestations of white matter components.The SIWMI animal models are categorized into 1)chemically induced SIWMI models,2)vascular occlusive SIWMI models,and 3)SIWMI models with comorbid vascular risk factors.Chemically induced models display consistent lesions in predetermined areas of the white matter,but the abrupt evolution of lesions does not appropriately reflect the progressive pathological processes in human white matter hyperintensities.Vascular occlusive SIWMI models often do not exhibit white matter lesions that are sufficiently unequivocal to be quantified.When combined with comorbid vascular risk factors(specifically hypertension),however,they can produce progressive and definitive white matter lesions including diffuse rarefaction,demyelination,loss of oligodendrocytes,and glial activation,which are by far the closest to those found in human white matter hyperintensities lesions.However,considerable surgical mortality and unpredictable natural deaths during a follow-up period would necessitate further refinements in these models.In the meantime,in vitro SIWMI models that recapitulate myelinated white matter track may be utilized to study molecular mechanisms of the ischemic white matter injury.Appropriate in vivo and in vitro SIWMI models will contribute in a complementary manner to making a breakthrough in developing effective treatment to prevent progression of white matter hyperintensities.
文摘Axons in central nervous system （CNS） do not regenerate spontaneously after injuries such as stroke and traumatic spinal cord iniury. Both intrinsic and extrinsic factors are responsible for the regeneration fail- ure, Although intensive research efforts have been invested on extrinsic regeneration inhibitors, the extent to which glial inhibitors contribute to the regeneration failure in viva still remains elusive. Recent exper- imental evidence has rekindled interests in intrinsic factors for the regulation of regeneration capacity in adult mammals. In this review, we propose that activating macrophages with pro-regenerative molecular signatures could be a novel approach for boosting intrinsic regenerative capacity of CNS neurons. Using a conditioning injury model in which regeneration of central branches of dorsal root ganglia sensory neu- rons is enhanced by a preceding injury to the peripheral branches, we have demonstrated that perineuronal macrophages surrounding dorsal root ganglia neurons are critically involved in the maintenance of en- hanced regeneration capacity. Neuron-derived chemokine （C-C motif） ligand 2 （CCL2） seems to mediate neuron-macrophage interactions conveying injury signals to perineuronal macrophages taking on a soley pro-regenerative phenotype, which we designate as regeneration-associated macrophages （RAMs）. Ma- nipulation of the CCL2 signaling could boost regeneration potential mimicking the conditioning injury, suggesting that the chemokine-mediated RAM activation could be utilized as a regenerative therapeutic strategy for CNS injuries.
基金Supported by the Grant-in-Aid for Challenging Exploratory Research(No 25540110)from MEXT.
文摘Details about the structure of a network model are revealed at the spontaneous spike activity level,in which the power-law of synchrony is optimized to that observed in the CA3 hippocampal slice cultures.The network model is subject to spike noise with exponentially distributed interspike intervals.The excitatory(E)and/or inhibitory(I)neurons interact through synapses whose weights show a log-normal distribution.The spike behavior observed in the network model with the appropriate log-normal distributed synaptic weights fits best to that observed in the experiment.The best-fit is then achieved with high activities of I neurons having a hub-like structure,in which the I neurons,subject to optimized spike noise,are intensively projected from low active E neurons.
文摘Background Artificial intelligence(AI)has rapidly permeated various sectors,including healthcare,highlighting its potential to facilitate mental health assessments.This study explores the underexplored domain of AI’s role in evaluating prognosis and long-term outcomes in depressive disorders,offering insights into how AI large language models(LLMs)compare with human perspectives.Methods Using case vignettes,we conducted a comparative analysis involving different LLMs(ChatGPT-3.5,ChatGPT-4,Claude and Bard),mental health professionals(general practitioners,psychiatrists,clinical psychologists and mental health nurses),and the general public that reported previously.We evaluate the LLMs ability to generate prognosis,anticipated outcomes with and without professional intervention,and envisioned long-term positive and negative consequences for individuals with depression.Results In most of the examined cases,the four LLMs consistently identified depression as the primary diagnosis and recommended a combined treatment of psychotherapy and antidepressant medication.ChatGPT-3.5 exhibited a significantly pessimistic prognosis distinct from other LLMs,professionals and the public.ChatGPT-4,Claude and Bard aligned closely with mental health professionals and the general public perspectives,all of whom anticipated no improvement or worsening without professional help.Regarding long-term outcomes,ChatGPT 3.5,Claude and Bard consistently projected significantly fewer negative long-term consequences of treatment than ChatGPT-4.Conclusions This study underscores the potential of AI to complement the expertise of mental health professionals and promote a collaborative paradigm in mental healthcare.The observation that three of the four LLMs closely mirrored the anticipations of mental health experts in scenarios involving treatment underscores the technology’s prospective value in offering professional clinical forecasts.The pessimistic outlook presented by ChatGPT 3.5 is concerning,as it could potentially diminish patients’drive to initiate or continue depression therapy.In summary,although LLMs show potential in enhancing healthcare services,their utilisation requires thorough verification and a seamless integration with human judgement and skills.
文摘We study specific changes in repetitive firing in the two-dimensional Hindmarsh-Rose （2dHR） oscillatory sys- tem that undergoes a bifurcation transition from the supercritical Andronov-Hopf （All） type to the subcritical Andronov-Hopf （SAH） type. We identify dynamical mechanisms which are responsible for changes of the repeti- tive firing rate during the AH to SAH bifurcation transitions. These include frequency-shift functions in response to small perturbations of a timescale parameter, its multiplicative parameter, and an external input current in the 2dHR oscillatory system. The frequency-shift functions are explicitly represented as functions relating to the phase response curves （PRCs）. Then, we demonstrate that when the timescale is normal and relatively fast, the repetitive firing rate slightly increases and decreases respectively during the AH to SAH bifurcation transition with a change of the intrinsic parameter, whereas it decreases during the SAH to AH bifurcation transition with an increase in the timescale. By analyzing the three different frequency-shift functions, we show that such changes of the repetitive firing rate depend largely on changes of the PRC size. The PRC size for the SAH bifurcation shrinks to the PRC size for the AH bifurcation.
文摘Large populations with multi-modal biomedical phenotypes are crucial for investigating the potential causes of human diseases.In particular,large population-based imaging studies can provide detailed imaging-derived phenotypes(IDPs)to quantitatively describe the anatomical structure and function for assessing their associations with genetics,life-style factors and disease outcomes.However,it is not a trivial task to initiate a large population-based imaging study,considering the challenges of logistics,cost,standardisation of the image acquisition protocol,robust image analysis pipelines for IDP extraction and quality control etc.Published in Phenomics,Wang et al.describe the brain image acquisition and phenotyping protocol for the China Phenobank Project(CHPP)(Wang et al.2023),an effort to assess and understand the current health status of a Chinese population,as well as to investigate the causes and progression of common diseases in China.
基金funded by the Shanghai Municipal Science and Technology Major Project(No.2017SHZDZX01).
文摘Currently,standard protocols for body imaging and corresponding image processing pipelines in population-based cohort studies are unavailable,limiting the applications of body imaging.Based on the China Phenobank Project(CHPP),the present study described a body imaging protocol for multiple organs,including cardiac structures,liver,spleen,pancreas,kidneys,lung,prostate,and uterus,and the corresponding image processing pipelines promoted its development.Briefly,the body imaging protocol comprised a 40-min cardiac magnetic resonance imaging(MRI)scan,a 5-min computed tomography(CT)scan,a 20-min abdominal MRI scan,and a 10-min pelvic MRI scan.The recommended image processing pipeline utilized deep learning segmentation models to facilitate the analysis of large amount of data.This study aimed to provide a reference for planning studies based on the CHPP platform.
