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Aminoacyl-tRNA synthetases (ARSs) aminoacylate tRNA molecules with their cognate amino acid, enabling information transmission and providing substrates for protein biosynthesis. They also take part in nontranslational functions, mediated by the presence of other proteins domains. Mutations in ARS genes have been described as responsive to numerous factors, including neurological, autoimmune, and oncological. Variants of the ARS genes, both in heterozygosity and homozygosity, have been reported to be responsible for different pathological pictures in humankind. We present the case of a patient referred in infancy for failure to thrive and acquired microcephaly (head circumference: -5 SD). During follow-up we highlighted: dysphagia (which became increasingly severe until it became incompatible with oral feeding, with gastrostomy implantation, resulting in resolution of feeding difficulties), strabismus, hypotonia. NCV (Nerve Conduction Velocity) showed four limbs neuropathy, neurophysiological examination performed at 2 years of age mainly sensory and demyelinating. Exome sequencing (ES) was performed, detecting two novel compound heterozygous variants in the NARS1 gene (OMIM *108410): NM_004539:c.[662 A > G]; [1155dup], p.[(Asn221Ser)]; [(Arg386Thrfs*19)], inherited from mother and father respectively. In this article, we would like to focus on the presence of progressive dysphagia and severe neurodevelopmental disorder, associated with two novel variants in the NARS1 gene.
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Trastornos de Deglución , Trastornos del Neurodesarrollo , Humanos , Trastornos de Deglución/genética , Trastornos de Deglución/diagnóstico , Trastornos del Neurodesarrollo/genética , Trastornos del Neurodesarrollo/diagnóstico , Aminoacil-ARNt Sintetasas/genética , Masculino , Mutación/genética , Lactante , Preescolar , FemeninoRESUMEN
BACKGROUND AND AIMS: Pathogenic variants in the NARS1 gene, which encodes for the asparaginyl-tRNA synthetase1 (NARS1) enzyme, were associated with complex central and peripheral nervous system phenotypes. Recently, Charcot-Marie-Tooth (CMT) disease has been linked to heterozygous pathogenic variants in NARS1 in nine patients. Here, we report two brothers and their mother from a French family with distal hereditary motor neuropathy (dHMN) carrying a previously unreported NARS1 variant. METHODS: The NARS1 variant (c.1555G>C; p.(Gly519Arg)) was identified through whole-genome sequencing (WGS) performed on the family members. Clinical findings, nerve conduction studies (NCS), needle electromyography (EMG), and functional assays in yeast complementation assays are reported here. RESULTS: The family members showed symptoms of dHMN, including distal weakness and osteoarticular deformities. They also exhibited brisk reflexes suggestive of upper motor neuron involvement. All patients were able to walk independently at the last follow-up. NCS and EMG confirmed pure motor neuropathy. Functional assays in yeast confirmed a loss-of-function effect of the variant on NARS1 activity. INTERPRETATION: Our findings expand the clinical spectrum of NARS1-associated neuropathies, highlighting the association of NARS1 mutations with dHMN. The benign disease course observed in our patients suggests a slowly progressive phenotype. Further reports could contribute to a more comprehensive understanding of the spectrum of NARS1-associated neuropathies.
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Aminoacil-ARNt Sintetasas , Neuropatía Hereditaria Motora y Sensorial , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Aminoacil-ARNt Sintetasas/genética , Enfermedad de Charcot-Marie-Tooth/genética , Enfermedad de Charcot-Marie-Tooth/fisiopatología , Francia , Neuropatía Hereditaria Motora y Sensorial/genética , Neuropatía Hereditaria Motora y Sensorial/fisiopatología , LinajeRESUMEN
BACKGROUND: NARS2 as a member of aminoacyl-tRNA synthetases was necessary to covalently join a specific tRNA to its cognate amino acid. Biallelic variants in NARS2 were reported with disorders such as Leigh syndrome, deafness, epilepsy, and severe myopathy. CASE PRESENTATION: Detailed clinical phenotypes were collected and the NARS2 variants were discovered by whole exome sequencing and verified by Sanger sequencing. Additionally, 3D protein structure visualization was performed by UCSF Chimera. The proband in our study had early-onset status epilepticus with abnormal EEG and MRI results. She also performed global developmental delay (GDD) and myocardial dysfunction. Next-generation sequencing (NGS) and Sanger sequencing revealed compound heterozygous missense variants [NM_024678.6:exon14: c.1352G > A(p.Arg451His); c.707T > C(p.Phe236Ser)] of the NARS2 gene. The proband develops refractory epilepsy with GDD and hyperlactatemia. Unfortunately, she finally died for status seizures two months later. CONCLUSION: We discovered two novel missense variants of NARS2 in a patient with early-onset status epilepticus and myocardial dysfunction. The NGS enables the patient to be clearly diagnosed as combined oxidative phosphorylation deficiency 24 (COXPD24, OMIM:616,239), and our findings expands the spectrum of gene variants in COXPD24.
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Aspartato-ARNt Ligasa , Epilepsia Refractaria , Epilepsia , Estado Epiléptico , Femenino , Humanos , Estado Epiléptico/diagnóstico , Estado Epiléptico/genética , Epilepsia Refractaria/genética , Mutación Missense , ARN de Transferencia , Mutación , Aspartato-ARNt Ligasa/genéticaRESUMEN
Mitochondria are essential for energy production and although they have their own genome, many nuclear-encoded mitochondrial ribosomal proteins (MRPs) are required for proper function of the organelle. Although mutations in MRPs have been associated with human diseases, little is known about their role during development. Presented here are the null phenotypes for 21 nuclear-encoded mitochondrial proteins and in-depth characterization of mouse embryos mutant for the Mrp genes Mrpl3, Mrpl22, Mrpl44, Mrps18c and Mrps22 Loss of each MRP results in successful implantation and egg-cylinder formation, followed by severe developmental delay and failure to initiate gastrulation by embryonic day 7.5. The robust and similar single knockout phenotypes are somewhat surprising given there are over 70 MRPs and suggest little functional redundancy. Metabolic analysis reveals that Mrp knockout embryos produce significantly less ATP than controls, indicating compromised mitochondrial function. Histological and immunofluorescence analyses indicate abnormal organelle morphology and stalling at the G2/M checkpoint in Mrp null cells. The nearly identical pre-gastrulation phenotype observed for many different nuclear-encoded mitochondrial protein knockouts hints that distinct energy systems are crucial at specific time points during mammalian development.
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Desarrollo Embrionario/genética , Gastrulación/genética , Mitocondrias/metabolismo , Proteínas Mitocondriales/genética , Ribosomas Mitocondriales/metabolismo , Proteínas Ribosómicas/genética , Animales , Puntos de Control del Ciclo Celular/genética , Femenino , Técnicas de Inactivación de Genes , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , FenotipoRESUMEN
BACKGROUND: NARS2 encodes mitochondrial Asparaginyl-tRNA Synthetase 2, which catalyzes the aminoacylation of tRNA-Asn in the mitochondria. To date, 24 variants have been reported in NARS2 gene in 35 patients. The phenotypic variability of NARS2-associated disorder is broad, ranging from neurodevelopmental disorders to hearing loss. In this study, we report some novel imaging findings in an Iranian patient suffering from epileptic encephalopathy, caused by a previously reported variant, c.500A > G; p.(His167Arg), in NARS2. METHODS: The spectrum of clinical manifestations of two Iranian patients was investigated and genetic analysis was performed by Whole-exome sequencing (WES). Additionally, we also reviewed the literature and summarized the phenotypes of previously reported patients with variants in the NARS2 gene. RESULTS: Here, we present the phenotypic and genetic features of 2 unrelated Iranian infants presented with neurodevelopmental delay, seizures, hearing impairment, feeding problems, elevated serum lactate levels in addition to subdural hematoma and cerebral parenchymal hemorrhage in the brain magnetic resonance imaging (MRI) of one of the patients. Genetic analysis revealed a biallelic missense variant in NARS2: c.500A > G; p.(His167Arg). We described the subdural hematoma and cerebral parenchymal hemorrhage of the brain for the first time. CONCLUSIONS: Our study provides new clinical findings, subdural hematoma, and parenchymal hemorrhage, in NARS2-related disorders. Our findings along with previous studies provide more evidence of the clinical presentation of the disease caused by pathogenic variants in NARS2. Expanding the clinical spectrum increases the diagnostic rate of molecular testing and improves the quality of counseling for at-risk couples.
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Aspartato-ARNt Ligasa , Encéfalo , Lactante , Humanos , Irán , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Hematoma Subdural/complicaciones , Hematoma Subdural/patología , Fenotipo , Hemorragia Cerebral , Aspartato-ARNt Ligasa/genéticaRESUMEN
This study reports on the adoption and impacts of CGIAR-related maize varieties in 18 major maize-producing countries in sub-Saharan Africa (SSA) during 1995-2015. Of the 1345 maize varieties released during this timeframe, approximately 60% had a known CGIAR parentage. About 34% (9.5 million ha) of the total maize area in 2015 was cultivated with 'new' CGIAR-related maize varieties released between 1995 and 2015. In the same year, an additional 13% of the maize area was cultivated with 'old' CGIAR-related maize varieties released before 1995. The aggregate annual economic benefit of using new CGIAR-related maize germplasm for yield increase in SSA was estimated at US$1.1-1.6 billion in 2015, which we attributed equally to co-investments by CGIAR funders, public-sector national research and extension programs, and private sector partners. Given that the annual global investment in CGIAR maize breeding at its maximum was US$30 million, the benefit-cost ratios for the CGIAR investment and CGIAR-attributable portion of economic benefits varied from 12:1-17:1, under the assumption of a 5-year lag in the research investment to yield returns. The study also discusses the methodological challenges involved in large-scale impact assessments. Post-2015 CGIAR tropical maize breeding efforts have had a strong emphasis on stress tolerance.
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Neonatal diabetes mellitus (NDM) with developmental delay and epilepsy is classified as developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome. The majority of DEND syndrome are due to severely damaging variants of K-ATP channels, and few mitochondria-related genes have been reported. We report here two Japanese siblings who were clinically diagnosed with DEND syndrome in whom NARS2 compound heterozygous variants were detected. Patient 1 was a 3-year-old girl and presented with diabetes ketoacidosis at 3 months old. Patient 2 was a 1-year-old boy who presented with severe hyperglycemia and started insulin therapy at 3 days old. After the first episodes, they both presented with severe developmental delay, hearing loss and treatment-resistant epilepsy accompanied by progressive brain atrophy. Whole-exome sequencing revealed compound heterozygous NARS2 p.R159C and p.L217V variants, and the GATA4 p.P407Q variant in both patients. They were treated by mitochondrial supportive therapy of vitamin B1, L-carnitine, and coenzyme Q10. Patient 2 was withdrawn from insulin therapy at 6 months old. This is the first report of NDM in which variants of the NARS2 gene coding mitochondrial protein were detected. Genetic analysis including mitochondrial genes should be considered in patients with neonatal onset diabetes associated with neurogenic symptoms.
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Aspartato-ARNt Ligasa , Diabetes Mellitus , Epilepsia , Aspartato-ARNt Ligasa/genética , Preescolar , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/genética , Epilepsia/diagnóstico , Epilepsia/tratamiento farmacológico , Epilepsia/genética , Femenino , Humanos , Hipoglucemiantes , Lactante , Recién Nacido , Enfermedades del Recién Nacido , Insulina , Masculino , Mutación , Trastornos Psicomotores , Hermanos , SíndromeRESUMEN
Leigh syndrome (LS), the most common mitochondrial disease in early childhood, usually manifests variable neurodegenerative symptoms and typical brain magnetic resonance imaging (MRI) lesions. To date, pathogenic variants in more than 80 genes have been identified. However, there are still many cases without molecular diagnoses, and thus more disease-causing variants need to be unveiled. Here, we presented three clinically suspected LS patients manifesting neurological symptoms including developmental delay, hypotonia, and epilepsy during the first year of age, along with symmetric brain lesions on MRI. We explored disease-associated variants in patients and their nonconsanguineous parents by whole-exome sequencing and subsequent Sanger sequencing verification. Sequencing data revealed three pairs of disease-associated compound heterozygous variants: c.1A>G (p.Met1?) and 409G>C (p.Asp137His) in SDHA, c.1253G>A (p.Arg418His) and 1300C>T (p.Leu434Phe) in NARS2, and c.5C>T (p.Ala2Val) and 773T>G (p.Leu258Trp) in ECHS1. Among them, the likely pathogenic variants c.409G>C (p.Asp137His) in SDHA, c.1300C>T (p.Leu434Phe) in NARS2, and c.773T>G (p.Leu258Trp) in ECHS1 were newly identified. Segregation analysis indicated the possible disease-causing nature of the novel variants. In silico prediction and three-dimensional protein modeling further suggested the potential pathogenicity of these variants. Our discovery of novel variants expands the gene variant spectrum of LS and provides novel evidence for genetic counseling.
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Aspartato-ARNt Ligasa , Enfermedad de Leigh , Aspartato-ARNt Ligasa/genética , Preescolar , China , Humanos , Enfermedad de Leigh/diagnóstico , Enfermedad de Leigh/genética , Enfermedad de Leigh/patología , Mutación , Linaje , Secuenciación del ExomaRESUMEN
NARS2 mutations are known to cause various clinical phenotypes such as nonsyndromic hearing loss, Leigh/Alpers syndrome, refractory epilepsy, developmental delay, intellectual disability and myopathy. We presented the first Turkish variant of NASR2 and added type 1 diabetes mellitus (DM), which was not previously described in the phenotype spectrum of this disease. A 4.5-month-old girl presented with hearing loss, hypotonia, refractory myoclonic epilepsy, severe developmental delay and large subdural hemorrhage. In the first year of the follow-up, type 1 DM developed. A homozygous missense mutation, [c.500 A>G, p.H167R] in the NARS2 gene was detected in the trio-based whole-exome sequencing (WES). In this disease, in addition to multi-organ involvement, type 1 DM may also develop, as in our case. Since it is a mitochondrial disease, the decision to treat with valproic acid should be reconsidered. The long diagnostic process can be shortened with WES.
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Aspartato-ARNt Ligasa , Diabetes Mellitus Tipo 1 , Discapacidad Intelectual , Enfermedad de Leigh , Humanos , Aspartato-ARNt Ligasa/genética , Diabetes Mellitus Tipo 1/complicaciones , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/genética , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Mutación , Mutación Missense , Fenotipo , Femenino , LactanteRESUMEN
Biallelic variants in the NARS2 gene are the cause of a continuous spectrum of neurodegenerative disorders presenting with various severity-from spastic paraplegia, progressive neurodegeneration to Leigh and Alpers syndrome. Common clinical signs result from a mitochondrial dysfunction based on OXPHOS deficiency. Here, we present a patient with infantile-onset severe epilepsy leading to fatal refractory status epilepticus. Whole exome sequencing with Exomiser analysis based on HPO terms detected two novel NARS2 variants in a compound heterozygous state. To date, 18 different NARS2 disease-causing mutations have been described. Our study adds to the understanding of this mitochondrial disorder.
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Aspartato-ARNt Ligasa/genética , Enfermedades Mitocondriales/genética , Mutación/genética , Edad de Inicio , Epilepsia/diagnóstico , Epilepsia/genética , Humanos , Recién NacidoRESUMEN
The National Wetland Condition Assessment (NWCA) is one of a series of probability-based National Aquatic Resource Surveys (NARS) conducted by the U.S. Environmental Protection Agency (USEPA) to provide a comprehensive assessment of the condition of the Nation's waters. Randomized design and standardized training and protocols allow USEPA to analyze data that are nationally consistent and regionally relevant. Each NARS assessment was preceded by careful consideration of key logistical elements that included pre-survey planning, training, sampling logistics, and laboratory analysis. Numerous state, tribal, and contractor crews were supported across the country for each assessment; sampling and sample analyses were tracked from initiation; laboratory analyses were completed at USEPA, state, regional, and contract laboratories; and the data analyses and reporting were completed by USEPA-led workgroups, states, and contractors. The complexity and difficulty of each step offered unique challenges and provided lessons learned for each of the NARS assessments. Major logistical elements for implementing large scale assessments that are constrained by sampling period and number and duration of visits are covered in this paper. These elements include sample transport, equipment and supplies, sampling and sample tracking, information management regional technical expertise, and a sound field training program. This paper describes how lessons from previous assessments were applied to the NWCA and how new challenges faced in the NWCA were addressed and carried forward into future surveys.
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Conservación de los Recursos Hídricos/métodos , Monitoreo del Ambiente/estadística & datos numéricos , Humedales , Conservación de los Recursos Hídricos/tendencias , Ecología , Monitoreo del Ambiente/normas , Humanos , Laboratorios/normas , Estados Unidos , United States Environmental Protection Agency/organización & administración , United States Environmental Protection Agency/normas , United States Environmental Protection Agency/estadística & datos numéricosRESUMEN
A homozygous missense mutation (c.822G>C) was found in the gene encoding the mitochondrial asparaginyl-tRNA synthetase (NARS2) in two siblings born to consanguineous parents. These siblings presented with different phenotypes: one had mild intellectual disability and epilepsy in childhood, whereas the other had severe myopathy. Biochemical analysis of the oxidative phosphorylation (OXPHOS) complexes in both siblings revealed a combined complex I and IV deficiency in skeletal muscle. In-gel activity staining after blue native-polyacrylamide gel electrophoresis confirmed the decreased activity of complex I and IV, and, in addition, showed the presence of complex V subcomplexes. Considering the consanguineous descent, homozygosity mapping and whole-exome sequencing were combined revealing the presence of one single missense mutation in the shared homozygous region. The c.822G>C variant affects the 3' splice site of exon 7, leading to skipping of the whole exon 7 and a part of exon 8 in the NARS2 mRNA. In EBV-transformed lymphoblasts, a specific decrease in the amount of charged mt-tRNA(Asn) was demonstrated as compared with controls. This confirmed the pathogenic nature of the variant. To conclude, the reported variant in NARS2 results in a combined OXPHOS complex deficiency involving complex I and IV, making NARS2 a new member of disease-associated aaRS2.
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Aspartato-ARNt Ligasa/genética , Mutación Missense , Adulto , Aspartato-ARNt Ligasa/metabolismo , Secuencia de Bases , Células Cultivadas , Consanguinidad , Análisis Mutacional de ADN , Femenino , Estudios de Asociación Genética , Homocigoto , Humanos , Masculino , Enfermedades Musculares/genética , Biosíntesis de Proteínas , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Sitios de Empalme de ARNRESUMEN
BACKGROUND: Significant recent efforts have facilitated increased access to clinical genetics assessment and genomic sequencing for children with rare diseases in many centres, but there remains a service gap for adults. The Austin Health Adult Undiagnosed Disease Program (AHA-UDP) was designed to complement existing UDP programs that focus on paediatric rare diseases and address an area of unmet diagnostic need for adults with undiagnosed rare conditions in Victoria, Australia. It was conducted at a large Victorian hospital to demonstrate the benefits of bringing genomic techniques currently used predominantly in a research setting into hospital clinical practice, and identify the benefits of enrolling adults with undiagnosed rare diseases into a UDP program. The main objectives were to identify the causal mutation for a variety of diseases of individuals and families enrolled, and to discover novel disease genes. METHODS: Unsolved patients in whom standard genomic diagnostic techniques such as targeted gene panel, exome-wide next generation sequencing, and/or chromosomal microarray, had already been performed were recruited. Genome sequencing and enhanced genomic analysis from the research setting were applied to aid novel gene discovery. RESULTS: In total, 16/50 (32%) families/cases were solved. One or more candidate variants of uncertain significance were detected in 18/50 (36%) families. No candidate variants were identified in 16/50 (32%) families. Two novel disease genes (TOP3B, PRKACB) and two novel genotype-phenotype correlations (NARS, and KMT2C genes) were identified. Three out of eight patients with suspected mosaic tuberous sclerosis complex had their diagnosis confirmed which provided reproductive options for two patients. The utility of confirming diagnoses for patients with mosaic conditions (using high read depth sequencing and ddPCR) was not specifically envisaged at the onset of the project, but the flexibility to offer recruitment and analyses on an as-needed basis proved to be a strength of the AHA-UDP. CONCLUSION: AHA-UDP demonstrates the utility of a UDP approach applying genome sequencing approaches in diagnosing adults with rare diseases who have had uninformative conventional genetic analysis, informing clinical management, recurrence risk, and recommendations for relatives.
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Enfermedades Raras , Humanos , Adulto , Femenino , Masculino , Australia , Enfermedades Raras/genética , Enfermedades Raras/diagnóstico , Enfermedades no Diagnosticadas/genética , Enfermedades no Diagnosticadas/diagnóstico , Pruebas Genéticas/métodos , Persona de Mediana Edad , Adulto JovenRESUMEN
This paper presents an interdisciplinary framework, Machine Psychology, which integrates principles from operant learning psychology with a particular Artificial Intelligence model, the Non-Axiomatic Reasoning System (NARS), to advance Artificial General Intelligence (AGI) research. Central to this framework is the assumption that adaptation is fundamental to both biological and artificial intelligence, and can be understood using operant conditioning principles. The study evaluates this approach through three operant learning tasks using OpenNARS for Applications (ONA): simple discrimination, changing contingencies, and conditional discrimination tasks. In the simple discrimination task, NARS demonstrated rapid learning, achieving 100% correct responses during training and testing phases. The changing contingencies task illustrated NARS's adaptability, as it successfully adjusted its behavior when task conditions were reversed. In the conditional discrimination task, NARS managed complex learning scenarios, achieving high accuracy by forming and utilizing complex hypotheses based on conditional cues. These results validate the use of operant conditioning as a framework for developing adaptive AGI systems. NARS's ability to function under conditions of insufficient knowledge and resources, combined with its sensorimotor reasoning capabilities, positions it as a robust model for AGI. The Machine Psychology framework, by implementing aspects of natural intelligence such as continuous learning and goal-driven behavior, provides a scalable and flexible approach for real-world applications. Future research should explore using enhanced NARS systems, more advanced tasks and applying this framework to diverse, complex tasks to further advance the development of human-level AI.
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BACKGROUND: The endocannabinoid system plays a key role in the control of many emotional-correlated reactions such as stress, depressed mood, and anxiety. Moreover, citicoline has neuroprotective properties and indicates beneficial effects in the treatment of depressive problems. Acute restraint stress (ARS) is an experimental model used for the induction of rodent models of depression. OBJECTIVE: This research was designed to assess the effects of intracerebroventricular (i.c.v.) injection of cannabinoid CB1 receptor agents on citicoline-induced response to depression-like behaviors in the non-acute restraint stress (NARS) and ARS mice. METHODS: For i.c.v. microinjection, a guide cannula was implanted in the left lateral ventricle of male mice. The ARS model was carried out by movement restraint for 4 h. Depression-related behaviors were assessed by forced swimming test (FST), tail suspension test (TST), and splash test. RESULTS: The results exhibited that the ARS mice showed depressive-like responses. I.c.v. infusion of ACPA (1 µg/mouse) induced an antidepressant-like effect in the NARS and ARS mice by reduction of immobility time in the FST and TST as well as enhancement of grooming activity time in the splash test. On the other hand, i.c.v. microinjection of AM251 dose-dependently (0.5 and 1 µg/mouse) induced a depressant-like effect in the NARS mice. I.p. injection of citicoline (80 mg/kg) induced an antidepressant-like response in the NARS and ARS mice. Furthermore, ACPA (0.25 µg/mouse, i.c.v.) potentiated the antidepressant-like response induced by citicoline (20 mg/kg, i.p.) in the NARS and ARS mice. However, AM251 (0.25 µg/mouse, i.c.v.) reversed the antidepressant-like effect produced by the citicoline (80 mg/kg, i.p.) in the NARS and ARS mice. Interestingly, our results indicated a synergistic effect between citicoline and ACPA based on the induction of an antidepressant-like effect in the NARS and ARS mice. CONCLUSIONS: These results suggested an interaction between citicoline and cannabinoid CB1 receptors on the modulation of depression-like behaviors in the NARS and ARS mice.
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Antidepresivos , Cannabinoides , Depresión , Animales , Masculino , Ratones , Antidepresivos/farmacología , Citidina Difosfato Colina , Depresión/tratamiento farmacológico , Modelos Animales de Enfermedad , Suspensión Trasera , Ratones Endogámicos , Natación , Receptor Cannabinoide CB1/agonistas , Ácidos Araquidónicos/farmacologíaRESUMEN
Pathogenic variants in six aminoacyl-tRNA synthetase (ARS) genes are implicated in neurological disorders, most notably inherited peripheral neuropathies. ARSs are enzymes that charge tRNA molecules with cognate amino acids. Pathogenic variants in asparaginyl-tRNA synthetase (NARS1) cause a neurological phenotype combining developmental delay, ataxia and demyelinating peripheral neuropathy. NARS1 has not yet been linked to axonal Charcot-Marie-Tooth disease. Exome sequencing of patients with inherited peripheral neuropathies revealed three previously unreported heterozygous NARS1 variants in three families. Clinical and electrophysiological details were assessed. We further characterized all three variants in a yeast complementation model and used a knock-in mouse model to study variant p.Ser461Phe. All three variants (p.Met236del, p.Cys342Tyr and p.Ser461Phe) co-segregate with the sensorimotor axonal neuropathy phenotype. Yeast complementation assays show that none of the three NARS1 variants support wild-type yeast growth when tested in isolation (i.e. in the absence of a wild-type copy of NARS1), consistent with a loss-of-function effect. Similarly, the homozygous knock-in mouse model (p.Ser461Phe/Ser472Phe in mouse) also demonstrated loss-of-function characteristics. We present three previously unreported NARS1 variants segregating with a sensorimotor neuropathy phenotype in three families. Functional studies in yeast and mouse support variant pathogenicity. Thus, NARS1 is the seventh ARS implicated in dominant axonal Charcot-Marie-Tooth disease, further stressing that all dimeric ARSs should be evaluated for Charcot-Marie-Tooth disease.
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The cannabinoid system plays a key role in stress-related emotional symptoms such as anxiety. Citicoline is a supplemental substance with neuroprotective properties that alleviates anxiety-related behaviors. There is a relation between the actions of cannabinoids and cholinergic systems. So, we decided to evaluate the effects of intracerebroventricular (i.c.v.) infusion of cannabinoid CB1 receptor agents on citicoline-produced response to anxiety-like behaviors in the non-acute restraint stress (NARS) and acute restraint stress (ARS) mice. For i.c.v. microinjection of drugs, a guide cannula was inserted in the left lateral ventricle. ARS was induced by movement restraint for 4 h. Anxiety-related behaviors were assessed using an elevated plus maze (EPM). The results showed that induction of ARS for 4 h decreased the percentage of time spent in the open arms (%OAT) and the percentage of entries to the open arms (%OAE) without affecting locomotor activity, showing anxiogenic-like behaviors. i.c.v. infusion of ACPA (1 µg/mouse) induced an anxiolytic-like effect due to the enhancement of %OAT in the NARS and ARS mice. Nonetheless, i.c.v. microinjection of AM251 (1 µg/mouse) decreased %OAT in the NARS and ARS mice which suggested an anxiogenic-like response. Intraperitoneal (i.p.) administration of citicoline (80 mg/kg) induced an anxiolytic-like effect by the augmentation of %OAT in the ARS mice. Furthermore, when ACPA and citicoline were co-administrated, ACPA potentiated the anxiolytic-like effect induced by citicoline in the NARS and ARS mice. On the other hand, when AM251 and the citicoline were co-injected, AM251 reversed the anxiolytic-like response induced by the citicoline in the NARS and ARS mice. The results of this research exhibited an additive effect between citicoline and ACPA on the induction of anxiolytic-like response in the NARS and ARS mice. Our results indicated an interaction between citicoline and cannabinoid CB1 receptor drugs on the control of anxiety-like behaviors in the NARS and ARS mice.
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Ansiolíticos , Cannabinoides , Ratones , Animales , Ansiolíticos/farmacología , Ansiolíticos/uso terapéutico , Citidina Difosfato Colina , Receptor Cannabinoide CB1 , Ansiedad/etiología , Ansiedad/inducido químicamente , Cannabinoides/farmacologíaRESUMEN
The use of service robots is rapidly expanding in many industries, including the retail sector. In some Asian countries retail companies already deploy in-store humanoid robot assistants that interact with customers in a personalized and dynamic way. However, little is known about customers' perceptions of these robot-assisted interactions. Therefore, we compared customers' perceived service quality of a human-robot interaction with a human-human interaction in a retail store, using an experiment with hypothetical scenarios (N = 425). Participants' general attitudes towards robots, their age, gender, and educational level were included as moderators in the analyses (a mixed-design ANOVA model). Results showed that participants valued service quality higher in the human-human interaction scenario. Additionally, findings from the moderation analyses indicated that perceived service quality of the human- robot interaction and the human-human interaction did not statistically significantly differ for participants with relatively high positive attitudes towards robots. Participants with relatively low positive attitudes towards robots, however, held statistically significantly lower perceptions of service quality for the human-robot interaction. Neither age, gender nor educational level statistically significantly influenced participants' perceived service quality scores for both service encounters.
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Progressive mitochondrial encephalopathy manifesting as developmental delay, regression, epilepsy, myoclonus, dystonia, and spasticity due to a novel compound heterozygous variant in NARS2 has not been reported. The patient is a 3.5-year-old female with normal psychomotor development until she experienced her first generalized status epilepticus at 4.5 months of age. After seizure control, generalized myoclonus and psychomotor regression became evident. She suffered from two other epileptic states and seizure control remained inadequate despite the use of multiple anti-seizure drugs. Neurologic examination revealed generalized hypotonia, discoordination, unstable eye contact, drooling, open mouth, myoclonus, periodic torticollis, and ankle contractions. Cerebral MRI revealed hydrocephalus ex vacuo due to diffuse cortical and subcortical atrophy bilaterally and incomplete myelination. Genetic testing at 12 months of age revealed the compound heterozygous variants chr11: 78204182C>T and chr11: 78282446A>AG in NARS2. Despite anti-seizure drugs, mitochondrial cocktail, and cannabidiol, the disease progressed to intractable seizures and severe tetraspasticity. In summary, this case demonstrates that compound heterozygous variants in NARS2 can phenotypically manifest exclusively in the brain with intractable epilepsy, myoclonus, developmental delay, regression, hypotonia, cerebral atrophy, and hypomyelination, followed by tetraspasticity and dystonia.
RESUMEN
In this article, the possibilities of recording EPR spectra by the non-adiabatic rapid sweep (NARS) method on a superheterodyne spectrometer are investigated. This method allows recording the pure EPR absorption spectrum of the object under investigation without the need for lineshape-lineheight compromise, while increasing sensitivity by suppressing low-frequency noise. In the NARS method, a low-amplitude sinusoidal modulation of a magnetic field is not used, and an oscillating triangular-shaped bipolar magnetic field is superimposed on the main permanent magnetic field. The triangular field repetition rate should be higher than that of the undesirable noise, and the amplitude is such that the rate of field change satisfies the Bloch non-adiabaticity criterion. The EPR absorption signal is digitized by a fast ADC and accumulated over a large number (n) of triangular field periods. In this case, for low-frequency noise, the spectrum of which is located below the repetition frequency of the triangular field, an accumulation process occurs with an increase in the signal-to-noise ratio (SNR) in proportion to n. A remarkable property of a superheterodyne spectrometer is that the frequency below which low-frequency noise prevails over white noise is significantly lower for it than for a homodyne spectrometer. This allows the use of a low repetition rate (LF NARS), which makes it much easier to obtain a highly linear triangular field of significant amplitude even in microwave resonators with a massive metal case since the harmful effects of eddy currents are reduced. The conditions of non-adiabaticity become easily feasible. At the same time, the noise suppression effect during accumulation turns out to be so significant that the SNR of the LFNARS spectrum exceeds that of the traditional spectrum with magnetic field modulation, with the same recording time, by more than 10 times.