RESUMEN
Brain organoid methods are complicated by multiple rosette structures and morphological variability. We have developed a human brain organoid technique that generates self-organizing, single-rosette cortical organoids (SOSR-COs) with reproducible size and structure at early timepoints. Rather than patterning a 3-dimensional embryoid body, we initiate brain organoid formation from a 2-dimensional monolayer of human pluripotent stem cells patterned with small molecules into neuroepithelium and differentiated to cells of the developing dorsal cerebral cortex. This approach recapitulates the 2D to 3D developmental transition from neural plate to neural tube. Most monolayer fragments form spheres with a single central lumen. Over time, the SOSR-COs develop appropriate progenitor and cortical laminar cell types as shown by immunocytochemistry and single-cell RNA sequencing. At early time points, this method demonstrates robust structural phenotypes after chemical teratogen exposure or when modeling a genetic neurodevelopmental disorder, and should prove useful for studies of human brain development and disease modeling.
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Células Madre Pluripotentes Inducidas , Células Madre Pluripotentes , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Encéfalo , Diferenciación Celular , OrganoidesAsunto(s)
Artroplastia de Reemplazo de Cadera/métodos , Enfermedad de la Arteria Coronaria/psicología , Procedimientos Quirúrgicos Electivos/métodos , Motivación , Osteoartritis de la Cadera/cirugía , Cuidados Preoperatorios/métodos , Estrés Psicológico/diagnóstico , Anciano , Enfermedad de la Arteria Coronaria/etiología , Enfermedad de la Arteria Coronaria/cirugía , Humanos , Revascularización Miocárdica/métodos , Osteoartritis de la Cadera/complicaciones , Cuidados Preoperatorios/educación , Estrés Psicológico/complicacionesRESUMEN
Selective neuronal vulnerability in neurodegenerative disease is poorly understood. Using the ATXN1[82Q] model of spinocerebellar ataxia type 1 (SCA1), we explored the hypothesis that regional differences in Purkinje neuron degeneration could provide novel insights into selective vulnerability. ATXN1[82Q] Purkinje neurons from the anterior cerebellum were found to degenerate earlier than those from the nodular zone, and this early degeneration was associated with selective dysregulation of ion channel transcripts and altered Purkinje neuron spiking. Efforts to understand the basis for selective dysregulation of channel transcripts revealed modestly increased expression of the ATXN1 co-repressor Capicua (Cic) in anterior cerebellar Purkinje neurons. Importantly, disrupting the association between ATXN1 and Cic rescued the levels of these ion channel transcripts, and lentiviral overexpression of Cic in the nodular zone accelerated both aberrant Purkinje neuron spiking and neurodegeneration. These findings reinforce the central role for Cic in SCA1 cerebellar pathophysiology and suggest that only modest reductions in Cic are needed to have profound therapeutic impact in SCA1.
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Ataxina-1/metabolismo , Activación del Canal Iónico , Neuronas/patología , Células de Purkinje/patología , Proteínas Represoras/metabolismo , Ataxias Espinocerebelosas/patología , Animales , Ataxina-1/genética , Femenino , Técnicas de Sustitución del Gen , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Neuronas/metabolismo , Células de Purkinje/metabolismo , Proteínas Represoras/genética , Ataxias Espinocerebelosas/genética , Ataxias Espinocerebelosas/metabolismoRESUMEN
The genetically heterogeneous spinocerebellar ataxias (SCAs) are caused by Purkinje neuron dysfunction and degeneration, but their underlying pathological mechanisms remain elusive. The Src family of nonreceptor tyrosine kinases (SFK) are essential for nervous system homeostasis and are increasingly implicated in degenerative disease. Here we reveal that the SFK suppressor Missing-in-metastasis (MTSS1) is an ataxia locus that links multiple SCAs. MTSS1 loss results in increased SFK activity, reduced Purkinje neuron arborization, and low basal firing rates, followed by cell death. Surprisingly, mouse models for SCA1, SCA2, and SCA5 show elevated SFK activity, with SCA1 and SCA2 displaying dramatically reduced MTSS1 protein levels through reduced gene expression and protein translation, respectively. Treatment of each SCA model with a clinically approved Src inhibitor corrects Purkinje neuron basal firing and delays ataxia progression in MTSS1 mutants. Our results identify a common SCA therapeutic target and demonstrate a key role for MTSS1/SFK in Purkinje neuron survival and ataxia progression.
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Proteínas de Microfilamentos/metabolismo , Proteínas de Neoplasias/metabolismo , Ataxias Espinocerebelosas/genética , Ataxias Espinocerebelosas/fisiopatología , Animales , Ataxia/patología , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Endogámicos C57BL , Proteínas de Microfilamentos/genética , Proteínas de Neoplasias/genética , Proteínas/metabolismo , Células de Purkinje/fisiología , Ataxias Espinocerebelosas/metabolismo , Degeneraciones Espinocerebelosas/metabolismo , Degeneraciones Espinocerebelosas/fisiopatología , Familia-src Quinasas/metabolismoRESUMEN
Niemann-Pick type C disease is a fatal, progressive neurodegenerative disorder caused by loss-of-function mutations in NPC1, a multipass transmembrane glycoprotein essential for intracellular lipid trafficking. We sought to define the cellular machinery controlling degradation of the most common disease-causing mutant, I1061T NPC1. We show that this mutant is degraded, in part, by the proteasome following MARCH6-dependent ERAD. Unexpectedly, we demonstrate that I1061T NPC1 is also degraded by a recently described autophagic pathway called selective ER autophagy (ER-phagy). We establish the importance of ER-phagy both in vitro and in vivo, and identify I1061T as a misfolded endogenous substrate for this FAM134B-dependent process. Subcellular fractionation of I1061T Npc1 mouse tissues and analysis of human samples show alterations of key components of ER-phagy, including FAM134B. Our data establish that I1061T NPC1 is recognized in the ER and degraded by two different pathways that function in a complementary fashion to regulate protein turnover.
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Proteínas Portadoras/metabolismo , Retículo Endoplásmico/metabolismo , Glicoproteínas de Membrana/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Autofagia , Encéfalo/patología , Proteínas Portadoras/genética , Degradación Asociada con el Retículo Endoplásmico , Fibroblastos/metabolismo , Homocigoto , Humanos , Péptidos y Proteínas de Señalización Intracelular , Lisosomas/metabolismo , Glicoproteínas de Membrana/genética , Proteínas de la Membrana/genética , Ratones , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutación , Proteína Niemann-Pick C1 , Complejo de la Endopetidasa Proteasomal/metabolismo , Transporte de Proteínas , Proteínas/genética , Ubiquitina-Proteína Ligasas/genética , Vinblastina/farmacologíaRESUMEN
OBJECTIVE: Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is the most common dominantly inherited ataxia. Despite advances in understanding this CAG repeat/polyglutamine expansion disease, there are still no therapies to alter its progressive fatal course. Here, we investigate whether an antisense oligonucleotide (ASO) targeting the SCA3 disease gene, ATXN3, can prevent molecular, neuropathological, electrophysiological, and behavioral features of the disease in a mouse model of SCA3. METHODS: The top ATXN3-targeting ASO from an in vivo screen was injected intracerebroventricularly into early symptomatic transgenic SCA3 mice that express the full human disease gene and recapitulate key disease features. Following a single ASO treatment at 8 weeks of age, mice were evaluated longitudinally for ATXN3 suppression and rescue of disease-associated pathological changes. Mice receiving an additional repeat injection at 21 weeks were evaluated longitudinally up to 29 weeks for motor performance. RESULTS: The ATXN3-targeting ASO achieved sustained reduction of polyglutamine-expanded ATXN3 up to 8 weeks after treatment and prevented oligomeric and nuclear accumulation of ATXN3 up to at least 14 weeks after treatment. Longitudinal ASO therapy rescued motor impairment in SCA3 mice, and this rescue was associated with a recovery of defects in Purkinje neuron firing frequency and afterhyperpolarization. INTERPRETATION: This preclinical study established efficacy of ATXN3-targeted ASOs as a disease-modifying therapeutic strategy for SCA3. These results support further efforts to develop ASOs for human clinical trials in this polyglutamine disease as well as in other dominantly inherited disorders caused by toxic gain of function. Ann Neurol 2018;83:64-77.
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Ataxina-3/química , Regulación de la Expresión Génica/efectos de los fármacos , Enfermedad de Machado-Joseph/tratamiento farmacológico , Oligonucleótidos Antisentido/uso terapéutico , Potenciales de Acción/efectos de los fármacos , Potenciales de Acción/genética , Factores de Edad , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Ataxina-3/genética , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Proteínas de Unión al Calcio/metabolismo , Modelos Animales de Enfermedad , Conducta Exploratoria/efectos de los fármacos , Femenino , Regulación de la Expresión Génica/genética , Gliosis/tratamiento farmacológico , Gliosis/etiología , Enfermedad de Machado-Joseph/genética , Enfermedad de Machado-Joseph/patología , Enfermedad de Machado-Joseph/fisiopatología , Masculino , Ratones , Ratones Transgénicos , Proteínas de Microfilamentos/metabolismo , Actividad Motora/efectos de los fármacos , Actividad Motora/genética , Mutación/genética , Células de Purkinje/efectos de los fármacos , Células de Purkinje/patología , Proteínas de Unión al ARN/metabolismoRESUMEN
Purkinje neuron dendritic degeneration precedes cell loss in cerebellar ataxia, but the basis for dendritic vulnerability in ataxia remains poorly understood. Recent work has suggested that potassium (K+) channel dysfunction and consequent spiking abnormalities contribute to Purkinje neuron degeneration, but little attention has been paid to how K+ channel dysfunction impacts dendritic excitability and the role this may play in the degenerative process. We examined the relationship between K+ channel dysfunction, dendritic excitability and dendritic degeneration in spinocerebellar ataxia type 1 (SCA1). Examination of published RNA sequencing data from SCA1 mice revealed reduced expression of several K+ channels that are important regulators of excitability in Purkinje neuron dendrites. Patch clamp recordings in Purkinje neurons from SCA1 mice identified increased dendritic excitability in the form of enhanced back-propagation of action potentials and an increased propensity to produce dendritic calcium spikes. Dendritic excitability could be rescued by restoring expression of large-conductance calcium-activated potassium (BK) channels and activating other K+ channels with baclofen. Importantly, this treatment combination improves motor performance and mitigates dendritic degeneration in SCA1 mice. These results suggest that reduced expression of K+ channels results in persistently increased dendritic excitability at all stages of disease in SCA1, which in turn may contribute to the dendritic degeneration that precedes cell loss.
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Dendritas/metabolismo , Dendritas/patología , Canales de Potasio/metabolismo , Ataxias Espinocerebelosas/metabolismo , Ataxias Espinocerebelosas/patología , Animales , Membrana Celular/metabolismo , Ratones , Fenotipo , Células de Purkinje/patologíaRESUMEN
Objective: Purkinje neuron dysfunction is associated with cerebellar ataxia. In a mouse model of spinocerebellar ataxia type 1 (SCA1), reduced potassium channel function contributes to altered membrane excitability resulting in impaired Purkinje neuron spiking. We sought to determine the relationship between altered membrane excitability and motor dysfunction in SCA1 mice. Methods: Patch-clamp recordings in acute cerebellar slices and motor phenotype testing were used to identify pharmacologic agents which improve Purkinje neuron physiology and motor performance in SCA1 mice. Additionally, we retrospectively reviewed records of patients with SCA1 and other autosomal-dominant SCAs with prominent Purkinje neuron involvement to determine whether currently approved potassium channel activators were tolerated. Results: Activating calcium-activated and subthreshold-activated potassium channels improved Purkinje neuron spiking impairment in SCA1 mice (P < 0.05). Additionally, dendritic hyperexcitability was improved by activating subthreshold-activated potassium channels but not calcium-activated potassium channels (P < 0.01). Improving spiking and dendritic hyperexcitability through a combination of chlorzoxazone and baclofen produced sustained improvements in motor dysfunction in SCA1 mice (P < 0.01). Retrospective review of SCA patient records suggests that co-treatment with chlorzoxazone and baclofen is tolerated. Interpretation: Targeting both altered spiking and dendritic membrane excitability is associated with sustained improvements in motor performance in SCA1 mice, while targeting altered spiking alone produces only short-term improvements in motor dysfunction. Potassium channel activators currently in clinical use are well tolerated and may provide benefit in SCA patients. Future clinical trials with potassium channel activators are warranted in cerebellar ataxia.
RESUMEN
Among the many types of neurons expressing protein kinase C (PKC) enzymes, cerebellar Purkinje neurons are particularly reliant on appropriate PKC activity for maintaining homeostasis. The importance of PKC enzymes in Purkinje neuron health is apparent as mutations in PRKCG (encoding PKCγ) cause cerebellar ataxia. PRKCG has also been identified as an important node in ataxia gene networks more broadly, but the functional role of PKC in other forms of ataxia remains unexplored, and the mechanisms by which PKC isozymes regulate Purkinje neuron health are not well understood. Here, we investigated how PKC activity influences neurodegeneration in inherited ataxia. Using mouse models of spinocerebellar ataxia type 1 (SCA1) and 2 (SCA2) we identify an increase in PKC-mediated substrate phosphorylation in two different forms of inherited cerebellar ataxia. Normalizing PKC substrate phosphorylation in SCA1 and SCA2 mice accelerates degeneration, suggesting that the increased activity observed in these models is neuroprotective. We also find that increased phosphorylation of PKC targets limits Purkinje neuron membrane excitability, suggesting that PKC activity may support Purkinje neuron health by moderating excitability. These data suggest a functional role for PKC enzymes in ataxia gene networks, and demonstrate that increased PKC activity is a protective modifier of degeneration in inherited cerebellar ataxia.
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Ataxina-1/genética , Ataxina-2/genética , Proteína Quinasa C/genética , Células de Purkinje/enzimología , Ataxias Espinocerebelosas/genética , Animales , Ataxina-1/metabolismo , Ataxina-2/metabolismo , Cerebelo/enzimología , Cerebelo/patología , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Humanos , Ratones , Ratones Transgénicos , Microtomía , Fosforilación , Cultivo Primario de Células , Proteína Quinasa C/metabolismo , Células de Purkinje/patología , Transducción de Señal , Ataxias Espinocerebelosas/enzimología , Ataxias Espinocerebelosas/patología , Ataxias Espinocerebelosas/prevención & control , Técnicas de Cultivo de TejidosRESUMEN
Neuronal atrophy in neurodegenerative diseases is commonly viewed as an early event in a continuum that ultimately results in neuronal loss. In a mouse model of the polyglutamine disorder spinocerebellar ataxia type 1 (SCA1), we tested the hypothesis that cerebellar Purkinje neuron atrophy serves an adaptive role rather than being simply a nonspecific response to injury. In acute cerebellar slices from SCA1 mice, we find that Purkinje neuron pacemaker firing is initially normal but, with the onset of motor dysfunction, becomes disrupted, accompanied by abnormal depolarization. Remarkably, subsequent Purkinje cell atrophy is associated with a restoration of pacemaker firing. The early inability of Purkinje neurons to support repetitive spiking is due to unopposed calcium currents resulting from a reduction in large-conductance calcium-activated potassium (BK) and subthreshold-activated potassium channels. The subsequent restoration of SCA1 Purkinje neuron firing correlates with the recovery of the density of these potassium channels that accompanies cell atrophy. Supporting a critical role for BK channels, viral-mediated increases in BK channel expression in SCA1 Purkinje neurons improves motor dysfunction and partially restores Purkinje neuron morphology. Cerebellar perfusion of flufenamic acid, an agent that restores the depolarized membrane potential of SCA1 Purkinje neurons by activating potassium channels, prevents Purkinje neuron dendritic atrophy. These results suggest that Purkinje neuron dendritic remodeling in ataxia is an adaptive response to increases in intrinsic membrane excitability. Similar adaptive remodeling could apply to other vulnerable neuronal populations in neurodegenerative disease. SIGNIFICANCE STATEMENT: In neurodegenerative disease, neuronal atrophy has long been assumed to be an early nonspecific event preceding neuronal loss. However, in a mouse model of spinocerebellar ataxia type 1 (SCA1), we identify a previously unappreciated compensatory role for neuronal shrinkage. Purkinje neuron firing in these mice is initially normal, but is followed by abnormal membrane depolarization resulting from a reduction in potassium channels. Subsequently, these electrophysiological effects are counteracted by cell atrophy, which by restoring normal potassium channel membrane density, re-establishes pacemaker firing. Reversing the initial membrane depolarization improved motor function and Purkinje neuron morphology in the SCA1 mice. These results suggest that Purkinje neuron remodeling in ataxia is an active compensatory response that serves to normalize intrinsic membrane excitability.
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Cerebelo/patología , Potenciales de la Membrana/fisiología , Células de Purkinje/patología , Ataxias Espinocerebelosas/patología , Potenciales de Acción/fisiología , Animales , Ataxina-1 , Ataxinas , Atrofia/patología , Atrofia/fisiopatología , Cerebelo/fisiopatología , Modelos Animales de Enfermedad , Ratones , Ratones Transgénicos , Proteínas del Tejido Nervioso/genética , Proteínas Nucleares/genética , Células de Purkinje/fisiología , Ataxias Espinocerebelosas/fisiopatologíaRESUMEN
INTRODUCTION: Cystic fibrosis (CF) is an autosomal recessive disease and is the most commonly seen monogenetic disease in Caucasians. The disease has various manifestations resulting from the abnormal thick secretions, most common being chronic lung infection and airway obstruction. Many new promising drugs have appeared on the horizon over the years. This review here is an attempt to bring together the various treatments being used to prolong and enhance the quality of life of CF patients. AREAS COVERED: A literature review of published as well as ongoing clinical trials, meta-analysis and systematic reviews regarding the drugs used in CF management was carried out using PubMed and Ovid databases. EXPERT OPINION: New concepts have been formed and some positive results in this direction have already led to the approval of cystic fibrosis transmembrane conductance regulator potentiator drug. Gene therapy and stem cell therapy are under development. The current therapies such as dornase alfa and pancreatic enzymes targeting the symptoms continue to evolve as they play an important complementary role. Development of new simple and cost-effective markers, which help assess the efficacy and safety of these constantly emerging new drugs, is also being investigated.
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Fibrosis Quística/tratamiento farmacológico , Diseño de Fármacos , Calidad de Vida , Adulto , Biomarcadores/metabolismo , Fibrosis Quística/fisiopatología , Fibrosis Quística/terapia , Regulador de Conductancia de Transmembrana de Fibrosis Quística/efectos de los fármacos , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Terapia Genética/métodos , Humanos , Trasplante de Células Madre/métodosRESUMEN
The cerebellum is an important structure for accurate control and timing of movement, and Purkinje neurons in the cerebellar cortex are key players in cerebellar motor control. Cerebellar dysfunction can result in ataxia, a disorder characterized by postural instability, gait disturbances and motor incoordination. Cerebellar ataxia is a symptom of a number of conditions, and the emerging evidence that Purkinje neuron dysfunction, in particular, abnormal Purkinje neuron repetitive firing, is a major driver of motor dysfunction in a subset of dominantly inherited ataxias is dicussed. Abnormalities in Purkinje neuron excitability that are observed in mouse models of each of these disorders, and where appropriate describe studies linking particular ion channels to aberrant excitability are also discussed. Common mechanisms of dysfunction and speculate about potential therapeutic targets, suggesting that Purkinje neuron firing abnormalities are a novel target for improving motor dysfunction in patients with some forms of dominantly inherited ataxia are proposed.
RESUMEN
Polyglutamine diseases are a class of neurodegenerative diseases that share an expansion of a glutamine-encoding CAG tract in the respective disease genes as a central hallmark. In all of these diseases there is progressive degeneration in a select subset of neurons, and the mechanisms behind this degeneration remain unclear. Emerging evidence from animal models of disease has identified abnormalities in synaptic signaling and intrinsic excitability in affected neurons, which coincide with the onset of symptoms and precede apparent neuropathology. The appearance of these early changes suggests that altered neuronal activity might be an important component of network dysfunction and that these alterations in network physiology could contribute to symptoms of disease. Here we review abnormalities in neuronal function that have been identified in both animal models and patients, and highlight ways in which these changes in neuronal activity may contribute to disease symptoms. We then review the literature supporting an emerging role for abnormalities in neuronal activity as a driver of neurodegeneration. Finally, we identify common themes that emerge from studies of neuronal dysfunction in polyglutamine disease.
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Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Neuronas/metabolismo , Expansión de Repetición de Trinucleótido , Animales , Encéfalo/metabolismo , Factor Neurotrófico Derivado del Encéfalo , Señalización del Calcio , Humanos , Canales Iónicos/genética , Péptidos , Médula Espinal/metabolismoRESUMEN
Dravet syndrome (also known as Severe Myoclonic Epilepsy of Infancy) is a rare genetic epilepsy syndrome commonly associated with loss-of-function mutations in SCN1A, the gene encoding the α subunit of the voltage-gated sodium channel NaV1.1, resulting in haploinsufficiency. Like other voltage-gated sodium channels, NaV1.1 function contributes to the rising phase of the neuronal action potential; thus, the observation that loss-of-function mutations in this channel gene are associated with seizures has created a paradox for the field. Major work has been done to untangle this paradox during the past decade, resulting in the development of two distinct hypotheses to explain seizures in Dravet syndrome. Here, we review the history of these two hypotheses and speculate as to what the history of Dravet syndrome research might tell us about its future.
RESUMEN
This cross-sectional study was done to assess the association of obesity with multiple conditions in an inner-city adult medicine clinic. Data were gathered to assess the relationship of obesity to multiple variables. Logistic regression was used to adjust for age, gender, ethnicity and tobacco use. Of 2,081 patients, 62% were minorities; 41% lacked insurance, and 38% had Medicaid. Forty-two percent were obese, with 9% morbidly obese. Out of 25 conditions, 20 had statistically significant correlations with obesity (two-sided P < 0.05): four cardiovascular, two pulmonary, three musculoskeletal, three metabolic syndrome conditions (metabolic syndrome is defined by the presence of three or more of the following: Fasting glucose > 110 mg/dL, BP > 130/85, Waist circumference in men > 40 inches or in women > 35 inches, HDL < 40 mg/dL in men or < 50 mg/dL in women, triglycerides > 150 mg/dL), four other clinical conditions, multiple ED visits, multiple clinic visits, unemployment, and disability. Body mass index (BMI) predicted coronary artery disease (P < 0.001), stroke (P = 0.011) and peripheral arterial disease (P = 0.013), but these associations were no longer statistically significant after adjustment for hypertension, diabetes and dyslipidemia. In conclusion, obesity was associated with many diseases, as well as with healthcare utilization, unemployment and disability in this predominantly minority inner-city population.
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Obesidad/epidemiología , Población Urbana/estadística & datos numéricos , Adulto , Anciano , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etnología , Comorbilidad , Connecticut/epidemiología , Estudios Transversales , Etnicidad/estadística & datos numéricos , Femenino , Humanos , Modelos Logísticos , Enfermedades Pulmonares/epidemiología , Enfermedades Pulmonares/etnología , Masculino , Síndrome Metabólico/epidemiología , Síndrome Metabólico/etnología , Persona de Mediana Edad , Grupos Minoritarios/estadística & datos numéricos , Obesidad/etnología , Pobreza/etnología , Pobreza/estadística & datos numéricos , Estados Unidos/epidemiologíaRESUMEN
We use molecular simulation to study the ability of excess entropy scaling relationships to describe the kinetic properties of four hydrocarbon isomers: n-octane, 2,2-dimethylhexane, 2,5-dimethylhexane, and 3-methyl-3-ethylpentane. Four dynamic properties are considered: translational and rotational diffusivities, a characteristic relaxation time for rotational motion, and a collective relaxation time stemming from analysis of the coherent intermediate scattering function. For each of the dynamic properties considered, reduced data collapse onto a species-specific common curve when expressed as a function of the thermodynamic excess entropy. Because each isomer exhibits a quantitatively distinct excess entropy scaling relationship, straightforward corresponding states principles do not provide an effective means to predict dynamic properties.
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Hexanos/química , Octanos/química , Termodinámica , IsomerismoRESUMEN
We use molecular simulation to study the ability of entropy scaling relationships to describe the kinetic properties of two Lennard-Jones dumbbell models. We begin by examining the excess entropy, the key quantity used to correlate dynamic properties within entropy scaling strategies. We compute the thermodynamic excess entropy as well as contributions to the two-body excess entropy stemming from translational and orientational intermolecular correlations. Our results indicate that the total two-body contribution accounts for more than 70% of the thermodynamic excess entropy at all state conditions explored. For the two dumbbell models studied here, the orientational component of the two-body excess entropy dominates at moderate and high fluid densities. We next investigate the relationships between kinetic properties and various contributions to the excess entropy. Four dynamic properties are considered: translational and rotational diffusivities, a characteristic relaxation time for rotational motion, and a collective relaxation time stemming from analysis of the coherent intermediate-scattering function. We find that the thermodynamic excess entropy provides the best metric for describing kinetic properties. For each of the dynamic properties considered, reduced data collapse onto a common curve when expressed as a function of the thermodynamic excess entropy. The likelihood of a two-body contribution to the excess entropy serving as a reliable scaling variable is linked to the extent to which it correlates with the thermodynamic excess entropy. The total two-body term contributes significantly to the excess entropy, and therefore this quantity generally serves as a suitable scaling variable.
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Entropía , Simulación de Dinámica Molecular , Cinética , Modelos Moleculares , Tamaño de la PartículaRESUMEN
We use molecular dynamics and transition-matrix Monte Carlo simulation to study the ability of entropy scaling relationships to describe kinetic properties of the extended simple point charge water model. We examine translational and rotational diffusivities, a characteristic relaxation time for rotational motion, and a collective relaxation time stemming from analysis of the coherent intermediate scattering function. We consider both the thermodynamic excess entropy and the contribution to the two-body excess entropy related to center-of-mass correlations as scaling variables. Calculations are performed over a broad range of conditions that span from the dense supercooled liquid regime to the critical region. We find that the thermodynamic excess entropy serves as a suitable metric for describing reduced transport properties for state conditions corresponding to temperatures above the onset of water's structurally anomalous region, defined by states points for which the excess entropy increases upon compression at constant temperature. In contrast, the aforementioned two-body contribution to the excess entropy cannot be used to quantitatively predict kinetic properties over the wide range of conditions explored here. For state points above the onset temperature of the structurally anomalous region, reduced transport property data collapse onto common curves when expressed as a function of the thermodynamic excess entropy. Below this temperature, data fall onto isochore-specific curves. Our results show a relatively strong correlation between the translational diffusivity and excess entropy and a noticeably weaker correlation between rotational mobility and excess entropy.
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Entropía , Agua/química , Modelos Químicos , Simulación de Dinámica Molecular , Método de Montecarlo , TermodinámicaRESUMEN
We use molecular simulation to study the ability of excess entropy scaling relationships to describe the kinetic properties of a confined molecular system. We examine a model for a confined fluid consisting of dumbbell-shaped molecules that interact with atomistically detailed pore walls via a Lennard-Jones potential. We obtain kinetic, thermodynamic, and structural properties of the system at three wall-fluid interaction strengths and over a temperature range that includes sub- and super-critical conditions. Four dynamic properties are considered: translational and rotational diffusivities, a characteristic relaxation time for rotational motion, and a collective relaxation time stemming from analysis of the coherent intermediate scattering function. We carefully consider the reference state used to define the excess entropy of a confined fluid. Three ideal-gas reference states are considered, with the cases differentiated by the extent to which one-body spatial and orientational correlations are accounted for in the reference state. Our results indicate that a version of the excess entropy that includes information related to the one-body correlations in a confined fluid serves as the best scaling variable for dynamic properties. When adopting such a definition for the reference state, to a very good approximation, bulk and confined data for a specified dynamic property at a given temperature collapse onto a common curve when plotted against the excess entropy.