Pub Date : 2024-07-11DOI: 10.1016/j.nbd.2024.106603
Vincent Huin , David Blum , Violette Delforge , Emeline Cailliau , Sofia Djeziri , Kathy Dujardin , Alexandre Genet , Romain Viard , Shahram Attarian , Gaelle Bruneteau , Julien Cassereau , Steeve Genestet , Anne-Laure Kaminsky , Marie-Hélène Soriani , Mathilde Lefilliatre , Philippe Couratier , Sophie Pittion-Vouyovitch , Florence Esselin , Elisa De La Cruz , Nathalie Guy , Anne-Sophie Rolland
Caffeine consumption outcomes on Amyotrophic Lateral Sclerosis (ALS) including progression, survival and cognition remain poorly defined and may depend on its metabolization influenced by genetic variants. 378 ALS patients with a precise evaluation of their regular caffeine consumption were monitored as part of a prospective multicenter study. Demographic, clinical characteristics, functional disability as measured with revised ALS Functional Rating Scale (ALSFRS-R), cognitive deficits measured using Edinburgh Cognitive and Behavioural ALS Screen (ECAS), survival and riluzole treatment were recorded. 282 patients were genotyped for six single nucleotide polymorphisms tagging different genes involved in caffeine intake and/or metabolism: CYP1A1 (rs2472297), CYP1A2 (rs762551), AHR (rs4410790), POR (rs17685), XDH (rs206860) and ADORA2A (rs5751876) genes. Association between caffeine consumption and ALSFRS-R, ALSFRS-R rate, ECAS and survival were statistically analyzed to determine the outcome of regular caffeine consumption on ALS disease progression and cognition. No association was observed between caffeine consumption and survival (p = 0.25), functional disability (ALSFRS-R; p = 0.27) or progression of ALS (p = 0.076). However, a significant association was found with higher caffeine consumption and better cognitive performance on ECAS scores in patients carrying the C/T and T/T genotypes at rs2472297 (p-het = 0.004). Our results support the safety of regular caffeine consumption on ALS disease progression and survival and also show its beneficial impact on cognitive performance in patients carrying the minor allele T of rs2472297, considered as fast metabolizers, that would set the ground for a new pharmacogenetic therapeutic strategy.
摄入咖啡因对肌萎缩侧索硬化症(ALS)的影响,包括病情发展、生存和认知能力,目前还没有明确的定义,而且可能取决于受基因变异影响的咖啡因代谢。作为一项前瞻性多中心研究的一部分,我们对 378 名 ALS 患者进行了监测,并对他们定期摄入咖啡因的情况进行了精确评估。研究记录了患者的人口统计学特征、临床特征、以修订版 ALS 功能评定量表(ALSFRS-R)测量的功能障碍、以爱丁堡认知和行为 ALS 筛选(ECAS)测量的认知障碍、存活率和利鲁唑治疗情况。对 282 名患者进行了六种单核苷酸多态性基因分型,这些基因与咖啡因摄入和/或代谢有关:CYP1A1(rs2472297)、CYP1A2(rs762551)、AHR(rs4410790)、POR(rs17685)、XDH(rs206860)和ADORA2A(rs5751876)基因。统计分析了咖啡因摄入量与 ALSFRS-R、ALSFRS-R 率、ECAS 和存活率之间的关系,以确定经常摄入咖啡因对 ALS 疾病进展和认知能力的影响。在咖啡因摄入量与存活率(p = 0.25)、功能障碍(ALSFRS-R;p = 0.27)或 ALS 病程进展(p = 0.076)之间未观察到任何关联。然而,在 rs2472297 基因型为 C/T 和 T/T 的患者中,咖啡因摄入量越高,ECAS 评分的认知表现越好,两者之间存在明显关联(p-het = 0.004)。我们的研究结果表明,定期摄入咖啡因对 ALS 疾病进展和存活具有安全性,同时还显示了咖啡因对携带 rs2472297 小等位基因 T(被认为是快速代谢者)的患者认知能力的有益影响,这将为新的药物遗传学治疗策略奠定基础。
{"title":"Caffeine consumption outcomes on amyotrophic lateral sclerosis disease progression and cognition","authors":"Vincent Huin , David Blum , Violette Delforge , Emeline Cailliau , Sofia Djeziri , Kathy Dujardin , Alexandre Genet , Romain Viard , Shahram Attarian , Gaelle Bruneteau , Julien Cassereau , Steeve Genestet , Anne-Laure Kaminsky , Marie-Hélène Soriani , Mathilde Lefilliatre , Philippe Couratier , Sophie Pittion-Vouyovitch , Florence Esselin , Elisa De La Cruz , Nathalie Guy , Anne-Sophie Rolland","doi":"10.1016/j.nbd.2024.106603","DOIUrl":"10.1016/j.nbd.2024.106603","url":null,"abstract":"<div><p>Caffeine consumption outcomes on Amyotrophic Lateral Sclerosis (ALS) including progression, survival and cognition remain poorly defined and may depend on its metabolization influenced by genetic variants. 378 ALS patients with a precise evaluation of their regular caffeine consumption were monitored as part of a prospective multicenter study. Demographic, clinical characteristics, functional disability as measured with revised ALS Functional Rating Scale (ALSFRS-R), cognitive deficits measured using Edinburgh Cognitive and Behavioural ALS Screen (ECAS), survival and riluzole treatment were recorded. 282 patients were genotyped for six single nucleotide polymorphisms tagging different genes involved in caffeine intake and/or metabolism: <em>CYP1A1</em> (rs2472297), <em>CYP1A2</em> (rs762551), <em>AHR</em> (rs4410790), <em>POR</em> (rs17685), <em>XDH</em> (rs206860) and <em>ADORA2A</em> (rs5751876) genes. Association between caffeine consumption and ALSFRS-R, ALSFRS-R rate, ECAS and survival were statistically analyzed to determine the outcome of regular caffeine consumption on ALS disease progression and cognition. No association was observed between caffeine consumption and survival (<em>p</em> = 0.25), functional disability (ALSFRS-R; <em>p</em> = 0.27) or progression of ALS (<em>p</em> = 0.076). However, a significant association was found with higher caffeine consumption and better cognitive performance on ECAS scores in patients carrying the C/T and T/T genotypes at rs2472297 (p-het = 0.004). Our results support the safety of regular caffeine consumption on ALS disease progression and survival and also show its beneficial impact on cognitive performance in patients carrying the minor allele T of rs2472297, considered as fast metabolizers, that would set the ground for a new pharmacogenetic therapeutic strategy.</p></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969996124002031/pdfft?md5=19e12c30478d2050d7a8abcb6ea89a95&pid=1-s2.0-S0969996124002031-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141603948","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-11DOI: 10.1016/j.nbd.2024.106598
Myocardial infarction (MI) and depression are leading causes of mortality and morbidity globally, and these conditions are increasing recognized as being fundamentally interconnected. The recently recognized gut-heart-brain axis offers insights into depression following MI, but effective treatments for this comorbidity remain lacking. To address this medical need, we employed an animal model of MI to investigate the potential repurposing of sotagliflozin (SOTA), an approved sodium-glucose cotransporter 1 and 2 (SGLT1/2) inhibitor for diabetes, for managing depression following MI and identifying potential SOTA-associated microbial mechanisms. SOTA treatment improved cardiac dysfunction and alleviated depression-like behaviors induced by MI, accompanied by alterations in gut microbiota composition, such as changes in the Prevotellaceae NK3B31 group, Alloprevotella, and Prevotellaceae UCG-001. Moreover, fecal microbiota transplantation (FMT) using fecal samples from SOTA-treated MI mice demonstrated that gut microbiota contributed to the beneficial effects of SOTA on cardiac dysfunction and depression-like behaviors in MI mice. Intriguingly, FMT-based intervention and concordance analysis of gut microbiota before and after FMT suggested that Prevotellaceae NK3B31 group, Alloprevotella, and Prevotellaceae UCG-001 were associated with the beneficial effects of SOTA. Furthermore, functional prediction of gut microbiota and correlation analysis support the significance of these dynamic microbial communities. In conclusion, these findings suggest that SOTA could serve as a potential drug to ameliorate cardiac dysfunction and depressive symptoms in MI patients via through the gut-heart-brain axis.
心肌梗死(MI)和抑郁症是导致全球死亡和发病的主要原因,而且这两种疾病越来越被认为是相互关联的。最近公认的肠-心-脑轴为心肌梗死后的抑郁提供了启示,但对这种并发症仍然缺乏有效的治疗方法。为了满足这一医疗需求,我们采用了一种心肌梗死动物模型来研究索他利氟嗪(SOTA)(一种已获批准的糖尿病钠-葡萄糖共转运体 1 和 2(SGLT1/2)抑制剂)在治疗心肌梗死后抑郁方面的潜在再利用可能性,并确定潜在的 SOTA 相关微生物机制。SOTA 治疗改善了心功能障碍,减轻了心肌梗死诱发的抑郁样行为,同时改变了肠道微生物群的组成,如前胡科 NK3B31 群、Alloprevotella 和前胡科 UCG-001 的变化。此外,利用经 SOTA 处理的 MI 小鼠的粪便样本进行粪便微生物群移植(FMT)证明,肠道微生物群有助于 SOTA 对 MI 小鼠的心脏功能障碍和抑郁样行为产生有益影响。耐人寻味的是,基于 FMT 的干预和 FMT 前后肠道微生物群的一致性分析表明,Prevotellaceae NK3B31 组、Alloprevotella 和 Prevotellaceae UCG-001 与 SOTA 的有益作用相关。此外,肠道微生物群的功能预测和相关性分析也支持这些动态微生物群落的重要性。总之,这些研究结果表明,SOTA 可作为一种潜在的药物,通过肠道-心脑轴改善心肌梗死患者的心功能障碍和抑郁症状。
{"title":"Sotagliflozin attenuates cardiac dysfunction and depression-like behaviors in mice with myocardial infarction through the gut-heart-brain axis","authors":"","doi":"10.1016/j.nbd.2024.106598","DOIUrl":"10.1016/j.nbd.2024.106598","url":null,"abstract":"<div><p>Myocardial infarction (MI) and depression are leading causes of mortality and morbidity globally, and these conditions are increasing recognized as being fundamentally interconnected. The recently recognized gut-heart-brain axis offers insights into depression following MI, but effective treatments for this comorbidity remain lacking. To address this medical need, we employed an animal model of MI to investigate the potential repurposing of sotagliflozin (SOTA), an approved sodium-glucose cotransporter 1 and 2 (SGLT1/2) inhibitor for diabetes, for managing depression following MI and identifying potential SOTA-associated microbial mechanisms. SOTA treatment improved cardiac dysfunction and alleviated depression-like behaviors induced by MI, accompanied by alterations in gut microbiota composition, such as changes in the <em>Prevotellaceae NK3B31 group</em>, <em>Alloprevotella</em>, and <em>Prevotellaceae UCG-001</em>. Moreover, fecal microbiota transplantation (FMT) using fecal samples from SOTA-treated MI mice demonstrated that gut microbiota contributed to the beneficial effects of SOTA on cardiac dysfunction and depression-like behaviors in MI mice. Intriguingly, FMT-based intervention and concordance analysis of gut microbiota before and after FMT suggested that <em>Prevotellaceae NK3B31 group</em>, <em>Alloprevotella</em>, and <em>Prevotellaceae UCG-001</em> were associated with the beneficial effects of SOTA. Furthermore, functional prediction of gut microbiota and correlation analysis support the significance of these dynamic microbial communities. In conclusion, these findings suggest that SOTA could serve as a potential drug to ameliorate cardiac dysfunction and depressive symptoms in MI patients via through the gut-heart-brain axis.</p></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969996124001980/pdfft?md5=b880ca0714e6dcd62b44e497472b4f33&pid=1-s2.0-S0969996124001980-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141603950","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-11DOI: 10.1016/j.nbd.2024.106604
Mitochondria are essential regulators of cellular energy metabolism and play a crucial role in the maintenance and function of neuronal cells. Studies in the last decade have highlighted the importance of mitochondrial dynamics and bioenergetics in adult neurogenesis, a process that significantly influences cognitive function and brain plasticity. In this review, we examine the mechanisms by which mitochondria regulate adult neurogenesis, focusing on the impact of mitochondrial function on the behavior of neural stem/progenitor cells and the maturation and plasticity of newborn neurons in the adult mouse hippocampus. In addition, we explore the link between mitochondrial dysfunction, adult hippocampal neurogenesis and genes associated with cognitive deficits in neurodevelopmental disorders. In particular, we provide insights into how alterations in the transcriptional regulator NR2F1 affect mitochondrial dynamics and may contribute to the pathophysiology of the emerging neurodevelopmental disorder Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS). Understanding how genes involved in embryonic and adult neurogenesis affect mitochondrial function in neurological diseases might open new directions for therapeutic interventions aimed at boosting mitochondrial function during postnatal life.
{"title":"Mitochondrial regulation of adult hippocampal neurogenesis: Insights into neurological function and neurodevelopmental disorders","authors":"","doi":"10.1016/j.nbd.2024.106604","DOIUrl":"10.1016/j.nbd.2024.106604","url":null,"abstract":"<div><p>Mitochondria are essential regulators of cellular energy metabolism and play a crucial role in the maintenance and function of neuronal cells. Studies in the last decade have highlighted the importance of mitochondrial dynamics and bioenergetics in adult neurogenesis, a process that significantly influences cognitive function and brain plasticity. In this review, we examine the mechanisms by which mitochondria regulate adult neurogenesis, focusing on the impact of mitochondrial function on the behavior of neural stem/progenitor cells and the maturation and plasticity of newborn neurons in the adult mouse hippocampus. In addition, we explore the link between mitochondrial dysfunction, adult hippocampal neurogenesis and genes associated with cognitive deficits in neurodevelopmental disorders. In particular, we provide insights into how alterations in the transcriptional regulator NR2F1 affect mitochondrial dynamics and may contribute to the pathophysiology of the emerging neurodevelopmental disorder Bosch-Boonstra-Schaaf optic atrophy syndrome (BBSOAS). Understanding how genes involved in embryonic and adult neurogenesis affect mitochondrial function in neurological diseases might open new directions for therapeutic interventions aimed at boosting mitochondrial function during postnatal life.</p></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969996124002043/pdfft?md5=8ee9c56a5a13ab192e098deb3c62de4f&pid=1-s2.0-S0969996124002043-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141603949","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-10DOI: 10.1016/j.nbd.2024.106599
Objective
Sporadic Creutzfeldt-Jakob disease (sCJD) is a fatal rapidly progressive neurodegenerative disorder with no effective therapeutic interventions. We aimed to identify potential genetically-supported drug targets for sCJD by integrating multi-omics data.
Methods
Multi-omics-wide association studies, Mendelian randomization, and colocalization analyses were employed to explore potential therapeutic targets using expression, single-cell expression, DNA methylation, and protein quantitative trait locus data from blood and brain tissues. Outcome data was from a case-control genome-wide association study, which included 4110 sCJD patients and 13,569 controls. Further investigations encompassed druggability, potential side effects, and associated biological pathways of the identified targets.
Results
Integrative multi-omics analysis identified 23 potential therapeutic targets for sCJD, with five targets (STX6, XYLT2, PDIA4, FUCA2, KIAA1614) having higher levels of evidence. One target (XYLT2) shows promise for repurposing, two targets (XYLT2, PDIA4) are druggable, and three (STX6, KIAA1614, and FUCA2) targets represent potential future breakthrough points. The expression level of STX6 and XYLT2 in neurons and oligodendrocytes was closely associated with an increased risk of sCJD. Brain regions with high expression of STX6 or causal links to sCJD were often those areas commonly affected by sCJD.
Conclusions
Our study identified five potential therapeutic targets for sCJD. Further investigations are warranted to elucidate the mechanisms underlying the new targets for developing disease therapies or initiate clinical trials.
{"title":"Genetic insights into drug targets for sporadic Creutzfeldt-Jakob disease: Integrative multi-omics analysis","authors":"","doi":"10.1016/j.nbd.2024.106599","DOIUrl":"10.1016/j.nbd.2024.106599","url":null,"abstract":"<div><h3>Objective</h3><p>Sporadic Creutzfeldt-Jakob disease (sCJD) is a fatal rapidly progressive neurodegenerative disorder with no effective therapeutic interventions. We aimed to identify potential genetically-supported drug targets for sCJD by integrating multi-omics data.</p></div><div><h3>Methods</h3><p>Multi-omics-wide association studies, Mendelian randomization, and colocalization analyses were employed to explore potential therapeutic targets using expression, single-cell expression, DNA methylation, and protein quantitative trait locus data from blood and brain tissues. Outcome data was from a case-control genome-wide association study, which included 4110 sCJD patients and 13,569 controls. Further investigations encompassed druggability, potential side effects, and associated biological pathways of the identified targets.</p></div><div><h3>Results</h3><p>Integrative multi-omics analysis identified 23 potential therapeutic targets for sCJD, with five targets (<em>STX6, XYLT2, PDIA4, FUCA2, KIAA1614</em>) having higher levels of evidence. One target (<em>XYLT2</em>) shows promise for repurposing, two targets (<em>XYLT2</em>, <em>PDIA4</em>) are druggable, and three (<em>STX6</em>, <em>KIAA1614</em>, and <em>FUCA2</em>) targets represent potential future breakthrough points. The expression level of <em>STX6</em> and <em>XYLT2</em> in neurons and oligodendrocytes was closely associated with an increased risk of sCJD. Brain regions with high expression of <em>STX6</em> or causal links to sCJD were often those areas commonly affected by sCJD.</p></div><div><h3>Conclusions</h3><p>Our study identified five potential therapeutic targets for sCJD. Further investigations are warranted to elucidate the mechanisms underlying the new targets for developing disease therapies or initiate clinical trials.</p></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969996124001992/pdfft?md5=942236f6ddb4aedb33a2db4afd87466e&pid=1-s2.0-S0969996124001992-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141600985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-10DOI: 10.1016/j.nbd.2024.106590
The infralimbic cortex (IL) is part of the medial prefrontal cortex (mPFC), exerting top-down control over structures that are critically involved in the development of alcohol use disorder (AUD). Activity of the IL is tightly controlled by γ-aminobutyric acid (GABA) transmission, which is susceptible to chronic alcohol exposure and withdrawal. This inhibitory control is regulated by various neuromodulators, including 5-hydroxytryptamine (5-HT; serotonin). We used chronic intermittent ethanol vapor inhalation exposure, a model of AUD, in male Sprague-Dawley rats to induce alcohol dependence (Dep) followed by protracted withdrawal (WD; 2 weeks) and performed ex vivo electrophysiology using whole-cell patch clamp to study GABAergic transmission in layer V of IL pyramidal neurons. We found that WD increased frequencies of spontaneous inhibitory postsynaptic currents (sIPSCs), whereas miniature IPSCs (mIPSCs; recorded in the presence of tetrodotoxin) were unaffected by either Dep or WD. The application of 5-HT (50 μM) increased sIPSC frequencies and amplitudes in naive and Dep rats but reduced sIPSC frequencies in WD rats. Additionally, 5-HT2A receptor antagonist M100907 and 5-HT2C receptor antagonist SB242084 reduced basal GABA release in all groups to a similar extent. The blockage of either 5-HT2A or 5-HT2C receptors in WD rats restored the impaired response to 5-HT, which then resembled responses in naive rats. Our findings expand our understanding of synaptic inhibition in the IL in AUD, indicating that antagonism of 5-HT2A and 5-HT2C receptors may restore GABAergic control over IL pyramidal neurons.
Significance statement
Impairment in the serotonergic modulation of GABAergic inhibition in the medial prefrontal cortex contributes to alcohol use disorder (AUD). We used a well-established rat model of AUD and ex vivo whole-cell patch-clamp electrophysiology to characterize the serotonin modulation of GABAergic transmission in layer V infralimbic (IL) pyramidal neurons in ethanol-naive, ethanol-dependent (Dep), and ethanol-withdrawn (WD) male rats. We found increased basal inhibition following WD from chronic alcohol and altered serotonin modulation. Exogenous serotonin enhanced GABAergic transmission in naive and Dep rats but reduced it in WD rats. 5-HT2A and 5-HT2C receptor blockage in WD rats restored the typical serotonin-mediated enhancement of GABAergic inhibition. Our findings expand our understanding of synaptic inhibition in the infralimbic neurons in AUD.
{"title":"Withdrawal from chronic alcohol impairs the serotonin-mediated modulation of GABAergic transmission in the infralimbic cortex in male rats","authors":"","doi":"10.1016/j.nbd.2024.106590","DOIUrl":"10.1016/j.nbd.2024.106590","url":null,"abstract":"<div><p>The infralimbic cortex (IL) is part of the medial prefrontal cortex (mPFC), exerting top-down control over structures that are critically involved in the development of alcohol use disorder (AUD). Activity of the IL is tightly controlled by γ-aminobutyric acid (GABA) transmission, which is susceptible to chronic alcohol exposure and withdrawal. This inhibitory control is regulated by various neuromodulators, including 5-hydroxytryptamine (5-HT; serotonin). We used chronic intermittent ethanol vapor inhalation exposure, a model of AUD, in male Sprague-Dawley rats to induce alcohol dependence (Dep) followed by protracted withdrawal (WD; 2 weeks) and performed <em>ex vivo</em> electrophysiology using whole-cell patch clamp to study GABAergic transmission in layer V of IL pyramidal neurons. We found that WD increased frequencies of spontaneous inhibitory postsynaptic currents (sIPSCs), whereas miniature IPSCs (mIPSCs; recorded in the presence of tetrodotoxin) were unaffected by either Dep or WD. The application of 5-HT (50 μM) increased sIPSC frequencies and amplitudes in naive and Dep rats but reduced sIPSC frequencies in WD rats. Additionally, 5-HT<sub>2A</sub> receptor antagonist M100907 and 5-HT<sub>2C</sub> receptor antagonist SB242084 reduced basal GABA release in all groups to a similar extent. The blockage of either 5-HT<sub>2A</sub> or 5-HT<sub>2C</sub> receptors in WD rats restored the impaired response to 5-HT, which then resembled responses in naive rats. Our findings expand our understanding of synaptic inhibition in the IL in AUD, indicating that antagonism of 5-HT<sub>2A</sub> and 5-HT<sub>2C</sub> receptors may restore GABAergic control over IL pyramidal neurons.</p></div><div><h3>Significance statement</h3><p>Impairment in the serotonergic modulation of GABAergic inhibition in the medial prefrontal cortex contributes to alcohol use disorder (AUD). We used a well-established rat model of AUD and <em>ex vivo</em> whole-cell patch-clamp electrophysiology to characterize the serotonin modulation of GABAergic transmission in layer V infralimbic (IL) pyramidal neurons in ethanol-naive, ethanol-dependent (Dep), and ethanol-withdrawn (WD) male rats. We found increased basal inhibition following WD from chronic alcohol and altered serotonin modulation. Exogenous serotonin enhanced GABAergic transmission in naive and Dep rats but reduced it in WD rats. 5-HT<sub>2A</sub> and 5-HT<sub>2C</sub> receptor blockage in WD rats restored the typical serotonin-mediated enhancement of GABAergic inhibition. Our findings expand our understanding of synaptic inhibition in the infralimbic neurons in AUD.</p></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969996124001906/pdfft?md5=0d586ce50e269b5cb4aadb556fb67244&pid=1-s2.0-S0969996124001906-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141600988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-10DOI: 10.1016/j.nbd.2024.106600
Frederik Arnskötter , Patricia Benites Goncalves da Silva , Mackenna E. Schouw , Chiara Lukasch , Luca Bianchini , Laura Sieber , Jesus Garcia-Lopez , Shiekh Tanveer Ahmad , Yiran Li , Hong Lin , Piyush Joshi , Lisa Spänig , Magdalena Radoš , Mykola Roiuk , Mari Sepp , Marc Zuckermann , Paul A. Northcott , Annarita Patrizi , Lena M. Kutscher
Familial Dysautonomia (FD) is an autosomal recessive disorder caused by a splice site mutation in the gene ELP1, which disproportionally affects neurons. While classically characterized by deficits in sensory and autonomic neurons, neuronal defects in the central nervous system have also been described. Although ELP1 expression remains high in the normal developing and adult cerebellum, its role in cerebellar development is unknown. To explore the role of Elp1 in the cerebellum, we knocked out Elp1 in cerebellar granule cell progenitors (GCPs) and examined the outcome on animal behavior and cellular composition. We found that GCP-specific conditional knockout of Elp1 (Elp1cKO) resulted in ataxia by 8 weeks of age. Cellular characterization showed that the animals had smaller cerebella with fewer granule cells. This defect was already apparent as early as 7 days after birth, when Elp1cKO animals also had fewer mitotic GCPs and shorter Purkinje dendrites. Through molecular characterization, we found that loss of Elp1 was associated with an increase in apoptotic cell death and cell stress pathways in GCPs. Our study demonstrates the importance of ELP1 in the developing cerebellum, and suggests that loss of Elp1 in the GC lineage may also play a role in the progressive ataxia phenotypes of FD patients.
{"title":"Loss of Elp1 in cerebellar granule cell progenitors models ataxia phenotype of Familial Dysautonomia","authors":"Frederik Arnskötter , Patricia Benites Goncalves da Silva , Mackenna E. Schouw , Chiara Lukasch , Luca Bianchini , Laura Sieber , Jesus Garcia-Lopez , Shiekh Tanveer Ahmad , Yiran Li , Hong Lin , Piyush Joshi , Lisa Spänig , Magdalena Radoš , Mykola Roiuk , Mari Sepp , Marc Zuckermann , Paul A. Northcott , Annarita Patrizi , Lena M. Kutscher","doi":"10.1016/j.nbd.2024.106600","DOIUrl":"10.1016/j.nbd.2024.106600","url":null,"abstract":"<div><p>Familial Dysautonomia (FD) is an autosomal recessive disorder caused by a splice site mutation in the gene <em>ELP1</em>, which disproportionally affects neurons. While classically characterized by deficits in sensory and autonomic neurons, neuronal defects in the central nervous system have also been described. Although <em>ELP1</em> expression remains high in the normal developing and adult cerebellum, its role in cerebellar development is unknown. To explore the role of <em>Elp1</em> in the cerebellum, we knocked out <em>Elp1</em> in cerebellar granule cell progenitors (GCPs) and examined the outcome on animal behavior and cellular composition<em>.</em> We found that GCP-specific conditional knockout of <em>Elp1 (Elp1</em><sup>cKO</sup>) resulted in ataxia by 8 weeks of age. Cellular characterization showed that the animals had smaller cerebella with fewer granule cells. This defect was already apparent as early as 7 days after birth, when <em>Elp1</em><sup>cKO</sup> animals also had fewer mitotic GCPs and shorter Purkinje dendrites. Through molecular characterization, we found that loss of <em>Elp1</em> was associated with an increase in apoptotic cell death and cell stress pathways in GCPs. Our study demonstrates the importance of <em>ELP1</em> in the developing cerebellum, and suggests that loss of <em>Elp1</em> in the GC lineage may also play a role in the progressive ataxia phenotypes of FD patients.</p></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969996124002006/pdfft?md5=af2d6021a78053731517b4599df90812&pid=1-s2.0-S0969996124002006-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141600987","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-10DOI: 10.1016/j.nbd.2024.106601
Activation of the purinergic receptor P2X7 (P2X7R) is believed to be deleterious in autoimmune diseases and it was hypothesized to play a role in the pathogenesis of MS. P2X7R is an ATP-gated non-selective cationic channel; its activation can be driven by high concentrations of ATP and leads to the generation of large, cytolytic conductance pores. P2X7R activation can also result in apoptosis as a consequence of the activation of the caspase cascade via P2X7R-dependent stimulation of the NLRP3 inflammasome. We measured P2X7R in oligodendrocyte derived extracellular vesicles (ODEVs) in MS patients and in healthy subjects.
Sixty-eight MS patients (50 relapsing-remitting, RR-MS, 18 primary progressive, PP-MS) and 57 healthy controls (HC) were enrolled. ODEVs were enriched from serum by a double step immunoaffinity method using an anti OMGp (oligodendrocyte myelin glycoprotein) antibody. P2X7R concentration was measured in ODEVs lysates by ELISA.
One–way Anova test showed that P2X7R in ODEVs is significantly higher in PP-MS (mean: 1742.89 pg/mL) compared both to RR-MS (mean: 1277.33 pg/mL) (p < 0.001) and HC (mean: 879.79 pg/mL) (p < 0.001). Comparison between RR-MS and HC was also statistically significant (p < 0.001). Pearson's correlations showed that P2RX7 in ODEVs was positively correlated with EDSS (p= 0.002, r = 0.38, 0.15–0.57 95% CI) and MSSS (p = 0.004, r = 0.34, 0.12–0.54 95% CI) scores, considering MS patients together (PP-MS + RR-MS) and with disease duration in PP-MS group (p = 0.02, r = 0.53, 0.09–0.80 95% CI).
Results suggest that ODEVs-associated P2X7R levels could be a biomarker for MS.
{"title":"Increased concentrations of P2X7R in oligodendrocyte derived extracellular vesicles of Multiple sclerosis patients","authors":"","doi":"10.1016/j.nbd.2024.106601","DOIUrl":"10.1016/j.nbd.2024.106601","url":null,"abstract":"<div><p>Activation of the purinergic receptor P2X7 (P2X7R) is believed to be deleterious in autoimmune diseases and it was hypothesized to play a role in the pathogenesis of MS. P2X7R is an ATP-gated non-selective cationic channel; its activation can be driven by high concentrations of ATP and leads to the generation of large, cytolytic conductance pores. P2X7R activation can also result in apoptosis as a consequence of the activation of the caspase cascade via P2X7R-dependent stimulation of the NLRP3 inflammasome. We measured P2X7R in oligodendrocyte derived extracellular vesicles (ODEVs) in MS patients and in healthy subjects.</p><p>Sixty-eight MS patients (50 relapsing-remitting, RR-MS, 18 primary progressive, PP-MS) and 57 healthy controls (HC) were enrolled. ODEVs were enriched from serum by a double step immunoaffinity method using an anti OMGp (oligodendrocyte myelin glycoprotein) antibody. P2X7R concentration was measured in ODEVs lysates by ELISA.</p><p>One–way Anova test showed that P2X7R in ODEVs is significantly higher in PP-MS (mean: 1742.89 pg/mL) compared both to RR-MS (mean: 1277.33 pg/mL) (<em>p</em> < 0.001) and HC (mean: 879.79 pg/mL) (<em>p</em> < 0.001). Comparison between RR-MS and HC was also statistically significant (<em>p</em> < 0.001). Pearson's correlations showed that P2RX7 in ODEVs was positively correlated with EDSS (<em>p</em> <em>=</em> 0.002, <em>r</em> = 0.38, 0.15–0.57 95% CI) and MSSS (<em>p</em> = 0.004, <em>r</em> = 0.34, 0.12–0.54 95% CI) scores, considering MS patients together (PP-MS + RR-MS) and with disease duration in PP-MS group (<em>p</em> = 0.02, <em>r</em> = 0.53, 0.09–0.80 95% CI).</p><p>Results suggest that ODEVs-associated P2X7R levels could be a biomarker for MS.</p></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969996124002018/pdfft?md5=a1021e7da0ca7661576b746b5d22872e&pid=1-s2.0-S0969996124002018-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141600986","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-09DOI: 10.1016/j.nbd.2024.106597
Ruth Nussinov , Bengi Ruken Yavuz , Hyunbum Jang
Pediatric low grade brain tumors and neurodevelopmental disorders share proteins, signaling pathways, and networks. They also share germline mutations and an impaired prenatal differentiation origin. They may differ in the timing of the events and proliferation. We suggest that their pivotal distinct, albeit partially overlapping, outcomes relate to the cell states, which depend on their spatial location, and timing of gene expression during brain development. These attributes are crucial as the brain develops sequentially, and single-cell spatial organization influences cell state, thus function. Our underlying premise is that the root cause in neurodevelopmental disorders and pediatric tumors is impaired prenatal differentiation. Data related to pediatric brain tumors, neurodevelopmental disorders, brain cell (sub)types, locations, and timing of expression in the developing brain are scant. However, emerging single cell technologies, including transcriptomic, spatial biology, spatial high-resolution imaging performed over the brain developmental time, could be transformational in deciphering brain pathologies thereby pharmacology.
{"title":"Single cell spatial biology over developmental time can decipher pediatric brain pathologies","authors":"Ruth Nussinov , Bengi Ruken Yavuz , Hyunbum Jang","doi":"10.1016/j.nbd.2024.106597","DOIUrl":"10.1016/j.nbd.2024.106597","url":null,"abstract":"<div><p>Pediatric low grade brain tumors and neurodevelopmental disorders share proteins, signaling pathways, and networks. They also share germline mutations and an impaired prenatal differentiation origin. They may differ in the timing of the events and proliferation. We suggest that their pivotal distinct, albeit partially overlapping, outcomes relate to the cell states, which depend on their spatial location, and timing of gene expression during brain development. These attributes are crucial as the brain develops sequentially, and single-cell spatial organization influences cell state, thus function. Our underlying premise is that the root cause in neurodevelopmental disorders and pediatric tumors is impaired prenatal differentiation. Data related to pediatric brain tumors, neurodevelopmental disorders, brain cell (sub)types, locations, and timing of expression in the developing brain are scant. However, emerging single cell technologies, including transcriptomic, spatial biology, spatial high-resolution imaging performed over the brain developmental time, could be transformational in deciphering brain pathologies thereby pharmacology.</p></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969996124001979/pdfft?md5=59afb2f679981a857b74801bb0b0667c&pid=1-s2.0-S0969996124001979-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141590919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-08DOI: 10.1016/j.nbd.2024.106596
Maxime Lévesque , Fei Ran Li , Siyan Wang , Massimo Avoli
Mesial temporal lobe epilepsy (MTLE) is characterized by recurring focal seizures that arise from limbic areas and are often refractory to pharmacological interventions. We have reported that optogenetic stimulation of PV-positive cells in the medial septum at 0.5 Hz exerts seizure-suppressive effects. Therefore, we compared here these results with those obtained by optogenetic stimulation of medial septum PV-positive neurons at 8 Hz in male PV-ChR2 mice (P60-P100) undergoing an initial, pilocarpine-induced status epilepticus (SE). Optogenetic stimulation (5 min ON, 10 min OFF) was performed from day 8 to day 12 after SE at a frequency of 8 Hz (n = 6 animals) or 0.5 Hz (n = 8 animals). Surprisingly, in both groups, no effects were observed on the occurrence of interictal spikes and interictal high frequency oscillations (HFOs). However, 0.5 Hz stimulation induced a significant decrease of seizure occurrence (p < 0.05). Such anti-ictogenic effect was not observed in the 8 Hz protocol that instead triggered seizures (p < 0.05); these seizures were significantly longer under optogenetic stimulation compared to when optogenetic stimulation was not implemented (p < 0.05). Analysis of ictal HFOs revealed that in the 0.5 Hz group, but not in the 8 Hz group, seizures occurring under optogenetic stimulation were associated with significantly lower rates of fast ripples compared to when optogenetic stimulation was not performed (p < 0.05). Our results indicate that activation of GABAergic PV-positive neurons in the medial septum exerts seizure-suppressing effects that are frequency-dependent and associated with low rates of fast ripples. Optogenetic activation of medial septum PV-positive neurons at 0.5 Hz is efficient in blocking seizures in the pilocarpine model of MTLE, an effect that did not occur with 8 Hz stimulation.
{"title":"Frequency-dependent seizure-suppressing effects of optogenetic activation of septal inhibitory cells in mesial temporal lobe epilepsy","authors":"Maxime Lévesque , Fei Ran Li , Siyan Wang , Massimo Avoli","doi":"10.1016/j.nbd.2024.106596","DOIUrl":"10.1016/j.nbd.2024.106596","url":null,"abstract":"<div><p>Mesial temporal lobe epilepsy (MTLE) is characterized by recurring focal seizures that arise from limbic areas and are often refractory to pharmacological interventions. We have reported that optogenetic stimulation of PV-positive cells in the medial septum at 0.5 Hz exerts seizure-suppressive effects. Therefore, we compared here these results with those obtained by optogenetic stimulation of medial septum PV-positive neurons at 8 Hz in male PV-ChR2 mice (P60-P100) undergoing an initial, pilocarpine-induced <em>status epilepticus</em> (SE). Optogenetic stimulation (5 min ON, 10 min OFF) was performed from day 8 to day 12 after SE at a frequency of 8 Hz (<em>n</em> = 6 animals) or 0.5 Hz (<em>n</em> = 8 animals). Surprisingly, in both groups, no effects were observed on the occurrence of interictal spikes and interictal high frequency oscillations (HFOs). However, 0.5 Hz stimulation induced a significant decrease of seizure occurrence (<em>p</em> < 0.05). Such anti-ictogenic effect was not observed in the 8 Hz protocol that instead triggered seizures (p < 0.05); these seizures were significantly longer under optogenetic stimulation compared to when optogenetic stimulation was not implemented (<em>p</em> < 0.05). Analysis of ictal HFOs revealed that in the 0.5 Hz group, but not in the 8 Hz group, seizures occurring under optogenetic stimulation were associated with significantly lower rates of fast ripples compared to when optogenetic stimulation was not performed (<em>p</em> < 0.05). Our results indicate that activation of GABAergic PV-positive neurons in the medial septum exerts seizure-suppressing effects that are frequency-dependent and associated with low rates of fast ripples. Optogenetic activation of medial septum PV-positive neurons at 0.5 Hz is efficient in blocking seizures in the pilocarpine model of MTLE, an effect that did not occur with 8 Hz stimulation.</p></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969996124001967/pdfft?md5=ec55e7dce5b5f9d027f70fb2f9ea46cb&pid=1-s2.0-S0969996124001967-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141580293","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-06DOI: 10.1016/j.nbd.2024.106595
Nolwazi Z. Gcwensa , Dreson L. Russell , Khaliah Y. Long , Charlotte F. Brzozowski , Xinran Liu , Karen L. Gamble , Rita M. Cowell , Laura A. Volpicelli-Daley
Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are characterized by neuronal α-synuclein (α-syn) inclusions termed Lewy Pathology, which are abundant in the amygdala. The basolateral amygdala (BLA), in particular, receives projections from the thalamus and cortex. These projections play a role in cognition and emotional processing, behaviors which are impaired in α-synucleinopathies. To understand if and how pathologic α-syn impacts the BLA requires animal models of α-syn aggregation. Injection of α-syn pre-formed fibrils (PFFs) into the striatum induces robust α-syn aggregation in excitatory neurons in the BLA that corresponds with reduced contextual fear conditioning. At early time points after aggregate formation, cortico-amygdala excitatory transmission is abolished. The goal of this project was to determine if α-syn inclusions in the BLA induce synaptic degeneration and/or morphological changes. In this study, we used C57BL/6 J mice injected bilaterally with PFFs in the dorsal striatum to induce α-syn aggregate formation in the BLA. A method was developed using immunofluorescence and three-dimensional reconstruction to analyze excitatory cortico-amygdala and thalamo-amygdala presynaptic terminals closely juxtaposed to postsynaptic densities. The abundance and morphology of synapses were analyzed at 6- or 12-weeks post-injection of PFFs. α-Syn aggregate formation in the BLA did not cause a significant loss of synapses, but cortico-amygdala and thalamo-amygdala presynaptic terminals and postsynaptic densities with aggregates of α-syn show increased volumes, similar to previous findings in human DLB cortex, and in non-human primate models of PD. Transmission electron microscopy showed that asymmetric synapses in mice with PFF-induced α-syn aggregates have reduced synaptic vesicle intervesicular distances, similar to a recent study showing phospho-serine-129 α-syn increases synaptic vesicle clustering. Thus, pathologic α-syn causes major alterations to synaptic architecture in the BLA, potentially contributing to behavioral impairment and amygdala dysfunction observed in synucleinopathies.
{"title":"Excitatory synaptic structural abnormalities produced by templated aggregation of α-syn in the basolateral amygdala","authors":"Nolwazi Z. Gcwensa , Dreson L. Russell , Khaliah Y. Long , Charlotte F. Brzozowski , Xinran Liu , Karen L. Gamble , Rita M. Cowell , Laura A. Volpicelli-Daley","doi":"10.1016/j.nbd.2024.106595","DOIUrl":"10.1016/j.nbd.2024.106595","url":null,"abstract":"<div><p>Parkinson's disease (PD) and Dementia with Lewy bodies (DLB) are characterized by neuronal α-synuclein (α-syn) inclusions termed Lewy Pathology, which are abundant in the amygdala. The basolateral amygdala (BLA), in particular, receives projections from the thalamus and cortex. These projections play a role in cognition and emotional processing, behaviors which are impaired in α-synucleinopathies. To understand if and how pathologic α-syn impacts the BLA requires animal models of α-syn aggregation. Injection of α-syn pre-formed fibrils (PFFs) into the striatum induces robust α-syn aggregation in excitatory neurons in the BLA that corresponds with reduced contextual fear conditioning. At early time points after aggregate formation, cortico-amygdala excitatory transmission is abolished. The goal of this project was to determine if α-syn inclusions in the BLA induce synaptic degeneration and/or morphological changes. In this study, we used C57BL/6 J mice injected bilaterally with PFFs in the dorsal striatum to induce α-syn aggregate formation in the BLA. A method was developed using immunofluorescence and three-dimensional reconstruction to analyze excitatory cortico-amygdala and thalamo-amygdala presynaptic terminals closely juxtaposed to postsynaptic densities. The abundance and morphology of synapses were analyzed at 6- or 12-weeks post-injection of PFFs. α-Syn aggregate formation in the BLA did not cause a significant loss of synapses, but cortico-amygdala and thalamo-amygdala presynaptic terminals and postsynaptic densities with aggregates of α-syn show increased volumes, similar to previous findings in human DLB cortex, and in non-human primate models of PD. Transmission electron microscopy showed that asymmetric synapses in mice with PFF-induced α-syn aggregates have reduced synaptic vesicle intervesicular distances, similar to a recent study showing phospho-serine-129 α-syn increases synaptic vesicle clustering. Thus, pathologic α-syn causes major alterations to synaptic architecture in the BLA, potentially contributing to behavioral impairment and amygdala dysfunction observed in synucleinopathies.</p></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":null,"pages":null},"PeriodicalIF":5.1,"publicationDate":"2024-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0969996124001955/pdfft?md5=9819c72fd682cf74905c0e80b75588fd&pid=1-s2.0-S0969996124001955-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141555270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}