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1.
J Virol ; 2021 Jan 11.
Artículo en Inglés | MEDLINE | ID: mdl-33431557

RESUMEN

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen responsible of coronavirus disease 2019 (COVID-19), has devastated public health services and economies worldwide. Despite global efforts to contain the COVID-19 pandemic, SARS-CoV-2 is now found in over 200 countries and has caused an upward death toll of over 1 million human lives as of November 2020. To date, only one Food and Drug Administration (FDA)-approved therapeutic drug (Remdesivir) and a monoclonal antibody, MAb (Bamlanivimab) are available for the treatment of SARS-CoV-2. As with other viruses, studying SARS-CoV-2 requires the use of secondary approaches to detect the presence of the virus in infected cells. To overcome this limitation, we have generated replication-competent recombinant (r)SARS-CoV-2 expressing fluorescent (Venus or mCherry) or bioluminescent (Nluc) reporter genes. Vero E6 cells infected with reporter-expressing rSARS-CoV-2 can be easily detected via fluorescence or luciferase expression and display a good correlation between reporter gene expression and viral replication. Moreover, rSARS-CoV-2 expressing reporter genes have comparable plaque sizes and growth kinetics to those of wild-type virus, rSARS-CoV-2/WT. We used these reporter-expressing rSARS-CoV-2 to demonstrate their feasibility to identify neutralizing antibodies (NAbs) or antiviral drugs. Our results demonstrate that reporter-expressing rSARS-CoV-2 represent an excellent option to identify therapeutics for the treatment of SARS-CoV-2, where reporter gene expression can be used as valid surrogates to track viral infection. Moreover, the ability to manipulate the viral genome opens the feasibility of generating viruses expressing foreign genes for their use as vaccines for the treatment of SARS-CoV-2 infection.IMPORTANCE Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen that causes coronavirus disease 2019 (COVID-19), has significantly impacted the human health and economic status worldwide. There is an urgent need to identify effective prophylactics and therapeutics for the treatment of SARS-CoV-2 infection and associated COVID-19 disease. The use of fluorescent- or luciferase-expressing reporter expressing viruses has significantly advanced viral research. Here, we generated recombinant (r)SARS-CoV-2 expressing fluorescent (Venus and mCherry) or luciferase (Nluc) reporter genes and demonstrate that they represent an excellent option to track viral infections in vitro. Importantly, reporter-expressing rSARS-CoV-2 display similar growth kinetics and plaque phenotype that their wild-type counterpart (rSARS-CoV-2/WT), demonstrating their feasibility to identify drugs and/or neutralizing antibodies (NAbs) for the therapeutic treatment of SARS-CoV-2. Henceforth, these reporter-expressing rSARS-CoV-2 can be used to interrogate large libraries of compounds and/or monoclonal antibodies (MAb), in high-throughput screening settings, to identify those with therapeutic potential against SARS-CoV-2.

2.
Nat Commun ; 11(1): 6122, 2020 11 30.
Artículo en Inglés | MEDLINE | ID: mdl-33257679

RESUMEN

Vaccine and antiviral development against SARS-CoV-2 infection or COVID-19 disease would benefit from validated small animal models. Here, we show that transgenic mice expressing human angiotensin-converting enzyme 2 (hACE2) by the human cytokeratin 18 promoter (K18 hACE2) represent a susceptible rodent model. K18 hACE2 transgenic mice succumbed to SARS-CoV-2 infection by day 6, with virus detected in lung airway epithelium and brain. K18 ACE2 transgenic mice produced a modest TH1/2/17 cytokine storm in the lung and spleen that peaked by day 2, and an extended chemokine storm that was detected in both lungs and brain. This chemokine storm was also detected in the brain at day 6. K18 hACE2 transgenic mice are, therefore, highly susceptible to SARS-CoV-2 infection and represent a suitable animal model for the study of viral pathogenesis, and for identification and characterization of vaccines (prophylactic) and antivirals (therapeutics) for SARS-CoV-2 infection and associated severe COVID-19 disease.

4.
Antioxidants (Basel) ; 9(10)2020 Sep 23.
Artículo en Inglés | MEDLINE | ID: mdl-32977491

RESUMEN

Oxidative stress is thought to contribute to the aetiology of neurological disorders such as Parkinson's disease. Ascorbate (vitamin C) is a potent antioxidant and is associated with neurological and cognitive function. In this study we assessed the ascorbate status of a cohort of people with Parkinson's disease (n = 215), aged 50-90 years, compared with a cohort of age matched healthy controls (n = 48). The study sample's cognitive status ranged from normal to mild cognitive impairment and dementia. There was no difference between the Parkinson's disease and healthy control groups with respect to mean ascorbate status, however, a higher proportion of participants with Parkinson's disease had hypovitaminosis C (i.e., <23 µmol/L) compared with healthy controls (20% vs. 8%, respectively). Within the Parkinson's disease group, Montreal Cognitive Assessment (MoCA) scores correlated positively with ascorbate concentrations, with higher ascorbate status associated with better cognitive function (r = 0.14, p = 0.045). Participants with hypovitaminosis C had significantly lower MoCA scores relative to participants with ascorbate concentrations >23 µmol/L (p = 0.014). Ascorbate concentrations were significantly lower in the cognitively impaired subgroup compared with the normal cognition subgroup in the Parkinson's disease cohort (p = 0.03). In contrast, urate showed an inverse correlation with cognitive function (r = -0.19, p = 0.007), with higher urate concentrations observed in the cognitively impaired subgroup compared with the normal cognition subgroup (p = 0.015). There was an inverse association between ascorbate status and urate concentrations (r = -0.15, p = 0.017). Plasma protein carbonyls, a measure of systemic oxidative stress, were not significantly different between the Parkinson's disease cohort and healthy controls, and there was no association with cognitive function (r = 0.09, p = 0.19) or with ascorbate status (r = -0.05, p = 0.45). Overall, our study showed ascorbate status was positively associated with cognitive function in Parkinson's disease, suggesting that longitudinal studies investigating the temporal sequence of cognitive decline and ascorbate status are warranted.

5.
mBio ; 11(5)2020 09 25.
Artículo en Inglés | MEDLINE | ID: mdl-32978313

RESUMEN

Infectious coronavirus (CoV) disease 2019 (COVID-19) emerged in the city of Wuhan (China) in December 2019, causing a pandemic that has dramatically impacted public health and socioeconomic activities worldwide. A previously unknown coronavirus, severe acute respiratory syndrome CoV-2 (SARS-CoV-2), has been identified as the causative agent of COVID-19. To date, there are no U.S. Food and Drug Administration (FDA)-approved vaccines or therapeutics available for the prevention or treatment of SARS-CoV-2 infection and/or associated COVID-19 disease, which has triggered a large influx of scientific efforts to develop countermeasures to control SARS-CoV-2 spread. To contribute to these efforts, we have developed an infectious cDNA clone of the SARS-CoV-2 USA-WA1/2020 strain based on the use of a bacterial artificial chromosome (BAC). Recombinant SARS-CoV-2 (rSARS-CoV-2) was readily rescued by transfection of the BAC into Vero E6 cells. Importantly, BAC-derived rSARS-CoV-2 exhibited growth properties and plaque sizes in cultured cells comparable to those of the natural SARS-CoV-2 isolate. Likewise, rSARS-CoV-2 showed levels of replication similar to those of the natural isolate in nasal turbinates and lungs of infected golden Syrian hamsters. This is, to our knowledge, the first BAC-based reverse genetics system for the generation of infectious rSARS-CoV-2 that displays features in vivo similar to those of a natural viral isolate. This SARS-CoV-2 BAC-based reverse genetics will facilitate studies addressing several important questions in the biology of SARS-CoV-2, as well as the identification of antivirals and development of vaccines for the treatment of SARS-CoV-2 infection and associated COVID-19 disease.IMPORTANCE The pandemic coronavirus (CoV) disease 2019 (COVID-19) caused by severe acute respiratory syndrome CoV-2 (SARS-CoV-2) is a major threat to global human health. To date, there are no approved prophylactics or therapeutics available for COVID-19. Reverse genetics is a powerful approach to understand factors involved in viral pathogenesis, antiviral screening, and vaccine development. In this study, we describe the feasibility of generating recombinant SARS-CoV-2 (rSARS-CoV-2) by transfection of a single bacterial artificial chromosome (BAC). Importantly, rSARS-CoV-2 possesses the same phenotype as the natural isolate in vitro and in vivo This is the first description of a BAC-based reverse genetics system for SARS-CoV-2 and the first time that an rSARS-CoV-2 isolate has been shown to be phenotypically identical to a natural isolate in a validated animal model of SARS-CoV-2 infection. The BAC-based reverse genetics approach will facilitate the study of SARS-CoV-2 and the development of prophylactics and therapeutics for the treatment of COVID-19.


Asunto(s)
Betacoronavirus/genética , Cromosomas Artificiales Bacterianos/genética , Animales , Betacoronavirus/patogenicidad , Betacoronavirus/fisiología , Chlorocebus aethiops , Infecciones por Coronavirus/virología , Cricetinae , ADN Complementario/genética , Genoma Viral/genética , Pandemias , Neumonía Viral/virología , ARN Viral/genética , Genética Inversa , Células Vero , Replicación Viral
6.
bioRxiv ; 2020 Jul 22.
Artículo en Inglés | MEDLINE | ID: mdl-32743573

RESUMEN

An infectious coronavirus disease 2019 (COVID-19) emerged in the city of Wuhan (China) in December 2019, causing a pandemic that has dramatically impacted public health and socioeconomic activities worldwide. A previously unknown coronavirus, Severe Acute Respiratory Syndrome CoV-2 (SARS-CoV-2), has been identified as the causative agent of COVID-19. To date, there are no United States (US) Food and Drug Administration (FDA)-approved vaccines or therapeutics available for the prevention or treatment of SARS-CoV-2 infection and/or associated COVID-19 disease, which has triggered a large influx of scientific efforts to develop countermeasures to control SARS-CoV-2 spread. To contribute to these efforts, we have developed an infectious cDNA clone of the SARS-CoV-2 USA-WA1/2020 strain based on the use of a bacterial artificial chromosome (BAC). Recombinant (r)SARS-CoV-2 was readily rescued by transfection of the BAC into Vero E6 cells. Importantly, the BAC-derived rSARS-CoV-2 exhibited growth properties and plaque sizes in cultured cells comparable to those of the SARS-CoV-2 natural isolate. Likewise, rSARS-CoV-2 showed similar levels of replication to that of the natural isolate in nasal turbinates and lungs of infected golden Syrian hamsters. This is, to our knowledge, the first BAC based reverse genetics system for the generation of infectious rSARS-CoV-2 that displays similar features in vivo to that of a natural viral isolate. This SARS-CoV-2 BAC-based reverse genetics will facilitate studies addressing several important questions in the biology of SARS-CoV-2, as well as the identification of antivirals and development of vaccines for the treatment of SARS-CoV-2 infection and associated COVID-19 disease.

7.
Brain ; 143(9): 2673-2680, 2020 Sep 01.
Artículo en Inglés | MEDLINE | ID: mdl-32851396

RESUMEN

Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) is a recently recognized neurodegenerative disease with onset in mid- to late adulthood. The genetic basis for a large proportion of Caucasian patients was recently shown to be the biallelic expansion of a pentanucleotide (AAGGG)n repeat in RFC1. Here, we describe the first instance of CANVAS genetic testing in New Zealand Maori and Cook Island Maori individuals. We show a novel, possibly population-specific CANVAS configuration (AAAGG)10-25(AAGGG)exp, which was the cause of CANVAS in all patients. There were no apparent phenotypic differences compared with European CANVAS patients. Presence of a common disease haplotype among this cohort suggests this novel repeat expansion configuration is a founder effect in this population, which may indicate that CANVAS will be especially prevalent in this group. Haplotype dating estimated the most recent common ancestor at ∼1430 ce. We also show the same core haplotype as previously described, supporting a single origin of the CANVAS mutation.

8.
Alzheimers Dement (Amst) ; 12(1): e12025, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32671179

RESUMEN

Objective: Cognitive impairment is a common feature of Parkinson disease (PD), for which age is a major contributing factor. Insulin-like growth factor-1 (IGF-1) declines with age and contributes to age-related cognitive impairment in PD. Cyclic glycine-proline (cGP) is a metabolite of IGF-1 and normalizes bioavailable IGF-1. Plasma cGP/IGF-1 molar ratio that represents bioactive IGF-1 in circulation, may associate with the cognitive status in PD. Methods: We examined the association of plasma cGP/IGF-1 molar ratio with the cognitive scores or age in PD patients with normal cognition (PD-N, n = 74), mild cognitive impairment (PD-MCI, n = 71), or dementia (PD-D, n = 33), and with the cognitive scores in 23 age-matched healthy controls. Plasma concentrations of IGF-1, IGF binding protein-3, and cGP were evaluated using enzyme-linked immunosorbent assay (ELISA) and high-performance liquid chromatography-mass spectrometry (HPLC-MS), respectively. Results: The cGP/IGF-1 molar ratio was positively correlated with the age of PD-N group, negatively correlated with the age of PD-D group, and not associated with the age of PD-MCI group. Independent of age, the cGP/IGF-1 molar ratio was positively correlated with the cognitive scores of healthy controls, but not in PD groups. Conclusion: Old healthy people with a higher cGP/IGF-1 molar ratio showed better preserved cognition, possibly due to improved IGF-1 function. Increased cGP/IGF-1 molar ratio with age may contribute to cognitive retention in the PD-N group. The absence or reversal of such association with age in the PD-MCI and PD-D groups may indicate the conversion of cognitive status in PD, if confirmed through longitudinal investigations within the individuals with advancing cognitive impairment.

9.
Mov Disord ; 35(7): 1268-1271, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32691912

RESUMEN

BACKGROUND: Uncontrolled studies have reported associations between later Parkinson's disease onset in women and a history of giving birth, with age at onset delayed by nearly 3 years per child. We tested this association in two independent data sets, but, as a control to test for nonbiological explanations, also included men with PD. METHODS: We analyzed valid cases from the Parkinson's Progressive Markers Initiative incident sample (145 women, 276 men) and a prevalent sample surveyed by the New Zealand Brain Research Institute (210 women, 394 men). RESULTS: The association was present in both women and men in the Parkinson's Progressive Markers Initiative study, and absent in both in the New Zealand Brain Research Institute study. This is consistent with generational differences common to men and women, which confound with age at onset in incident-dominant samples. CONCLUSIONS: Despite being replicable in certain circumstances, associations between childbirth and later PD onset are an artifact of generational cohort differences. © 2020 International Parkinson and Movement Disorder Society.

10.
Mov Disord ; 35(8): 1346-1356, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32557794

RESUMEN

BACKGROUND: GBA mutations are numerically the most significant genetic risk factor for Parkinson's disease (PD), yet these mutations have low penetrance, suggesting additional mechanisms. OBJECTIVES: The objective of this study was to determine if the penetrance of GBA in PD can be explained by regulatory effects on GBA and modifier genes. METHODS: Genetic variants associated with the regulation of GBA were identified by screening 128 common single nucleotide polymorphisms (SNPs) in the GBA locus for spatial cis-expression quantitative trail locus (supported by chromatin interactions). RESULTS: We identified common noncoding SNPs within GBA that (1) regulate GBA expression in peripheral tissues, some of which display α-synuclein pathology and (2) coregulate potential modifier genes in the central nervous system and/or peripheral tissues. Haplotypes based on 3 of these SNPs delay disease onset by 5 years. In addition, SNPs on 6 separate chromosomes coregulate GBA expression specifically in either the substantia nigra or cortex, and their combined effect potentially modulates motor and cognitive symptoms, respectively. CONCLUSIONS: This work provides a new perspective on the haplotype-specific effects of GBA and the genetic etiology of PD, expanding the role of GBA from the gene encoding the ß-glucocerebrosidase (GCase) to that of a central regulator and modifier of PD onset, with GBA expression itself subject to distant regulation. Some idiopathic patients might possess insufficient GBA-encoded GCase activity in the substantia nigra as the result of distant regulatory variants and therefore might benefit from GBA-targeting therapeutics. The SNPs' regulatory impacts provide a plausible explanation for the variable phenotypes also observed in GBA-centric Gaucher's disease and dementia with Lewy bodies. © 2020 The Authors. Movement Disorders published by Wiley Periodicals, LLC on behalf of International Parkinson and Movement Disorder Society.

11.
J Clin Neurosci ; 76: 183-188, 2020 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-32331938

RESUMEN

INTRODUCTION: Parkinson's disease (PD) patients are reported to score significantly lower on the Judgement of Line Orientation (JLO) test compared with controls. The traditional method of scoring JLO ignores potentially interesting information on the mechanism of errors made. AIM: The aim of the current study was to analyse the performance of PD patients on the JLO while monitoring eye movements. Employing eye tracking methods while PD participants attempt JLO items may prove valuable in further characterising error-patterns. METHODS: We recruited three groups, each comprising 16 participants: PD participants with normal cognition (PD-N), PD participants with mild cognitive impairment (PD-MCI) and matched controls. RESULTS: The mean correct response rates were high: 93% (±6) for controls, 88% (±12) for PD-N and 87% (±11) for PD-MCI; the difference did not reach statistical significance (p = 0.21). Participants made more errors as they progressed from easy to harder item (r = 0.7; p = 0.02). Using the Ska classification, error types QO1 and QO3 were by far and away the most common. The mean amplitudes of saccadic eye movements were 5.9° (±0.9) for controls, 5.7° (±1.1) for PD-N, and 5.5° (±1.0) for PD-MCI. The differences among the three groups did not reach statistical significance (p = 0.64). As a whole, participant fixation patterns were similar throughout the JLO task. For the reference lines, most fixations were made on the distal ends. Fixations on the test lines, on the other hand, appeared to vary among trials, dependent on whether the response was correct or incorrect. CONCLUSIONS: There were few differences among the study groups in test performance-eye movement associations. However, we gained important insights into oculomotor behaviour during JLO test completion in both healthy controls and PD patients which could reflect the underlying disease state as we hypothesised.


Asunto(s)
Enfermedad de Parkinson/psicología , Movimientos Sacádicos , Anciano , Cognición , Disfunción Cognitiva/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pruebas Neuropsicológicas
12.
Nat Commun ; 11(1): 1238, 2020 03 06.
Artículo en Inglés | MEDLINE | ID: mdl-32144264

RESUMEN

An improved understanding of etiological mechanisms in Parkinson's disease (PD) is urgently needed because the number of affected individuals is projected to increase rapidly as populations age. We present results from a blood-based methylome-wide association study of PD involving meta-analysis of 229 K CpG probes in 1,132 cases and 999 controls from two independent cohorts. We identify two previously unreported epigenome-wide significant associations with PD, including cg06690548 on chromosome 4. We demonstrate that cg06690548 hypermethylation in PD is associated with down-regulation of the SLC7A11 gene and show this is consistent with an environmental exposure, as opposed to medications or genetic factors with effects on DNA methylation or gene expression. These findings are notable because SLC7A11 codes for a cysteine-glutamate anti-porter regulating levels of the antioxidant glutathione, and it is a known target of the environmental neurotoxin ß-methylamino-L-alanine (BMAA). Our study identifies the SLC7A11 gene as a plausible biological target in PD.


Asunto(s)
Sistema de Transporte de Aminoácidos y+/metabolismo , Cromosomas Humanos Par 4/genética , Metilación de ADN , Enfermedad de Parkinson/genética , Adulto , Anciano , Anciano de 80 o más Años , Sistema de Transporte de Aminoácidos y+/genética , Australia , Estudios de Casos y Controles , Islas de CpG/genética , Regulación hacia Abajo , Epigenómica/métodos , Femenino , Glutatión/metabolismo , Voluntarios Sanos , Humanos , Masculino , Análisis de la Aleatorización Mendeliana , Persona de Mediana Edad , Nueva Zelanda , Enfermedad de Parkinson/sangre , Enfermedad de Parkinson/patología
13.
Disabil Rehabil ; 42(14): 1942-1953, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-30676112

RESUMEN

Purpose: Our objective was to explore the intersection between mild traumatic brain injury (MTBI) recovery experiences and injury understandings, using both quantitative and qualitative methods.Materials and Methods: The quantitative component was a descriptive case-control study comparing participants (n = 76) who had recovered or not recovered after an MTBI, across demographic and psychological variables. A subset of participants (n = 10) participated in a semi-structured interview to explore experiences of recovery in more detail. We followed threads across the datasets to integrate findings from component methods.Results: The quantitative analyses revealed differences between the two groups in terms of injury recovery understandings and expectations. The qualitative analyses suggested that achieving consistency across information sources was important. By tracing threads back and forth between the component datasets, we identified a super-ordinate meta-theme that captured participants' experiences of wrestling with uncertainty about their recovery and the impacts in terms of heightened anxiety, confusion, and feelings of invalidation.Conclusion: The effectiveness of psychoeducation and reassurance after MTBI may be optimized when content is tailored to the individual. Clinicians are urged to attend both to the subjective interpretations patients make of information gained from formal and informal, internal and external sources, and where information across these sources conflicts and creates uncertainty.Implications for rehabilitationEffectiveness of psychoeducation and reassurance after injury may be optimized when content is tailored to the individual rather than being generic.Effectiveness of such interventions may also be optimized by understanding the subjective interpretations individuals make of injury knowledge gleaned from formal and informal, internal and external sources.Conflicting information from such multiple sources may create uncertainty with associated increased distress as an individual negotiates their recovery from injury. Attending to this uncertainty may be a helpful target for treatment.

14.
PLoS Genet ; 15(10): e1008453, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31609965

RESUMEN

Determining the genetic basis of fitness is central to understanding evolution and transmission of microbial pathogens. In human malaria parasites (Plasmodium falciparum), most experimental work on fitness has focused on asexual blood stage parasites, because this stage can be easily cultured, although the transmission of malaria requires both female Anopheles mosquitoes and vertebrate hosts. We explore a powerful approach to identify the genetic determinants of parasite fitness across both invertebrate and vertebrate life-cycle stages of P. falciparum. This combines experimental genetic crosses using humanized mice, with selective whole genome amplification and pooled sequencing to determine genome-wide allele frequencies and identify genomic regions under selection across multiple lifecycle stages. We applied this approach to genetic crosses between artemisinin resistant (ART-R, kelch13-C580Y) and ART-sensitive (ART-S, kelch13-WT) parasites, recently isolated from Southeast Asian patients. Two striking results emerge: we observed (i) a strong genome-wide skew (>80%) towards alleles from the ART-R parent in the mosquito stage, that dropped to ~50% in the blood stage as selfed ART-R parasites were selected against; and (ii) repeatable allele specific skews in blood stage parasites with particularly strong selection (selection coefficient (s) ≤ 0.18/asexual cycle) against alleles from the ART-R parent at loci on chromosome 12 containing MRP2 and chromosome 14 containing ARPS10. This approach robustly identifies selected loci and has strong potential for identifying parasite genes that interact with the mosquito vector or compensatory loci involved in drug resistance.


Asunto(s)
Interacciones Huésped-Parásitos/genética , Estadios del Ciclo de Vida/genética , Malaria Falciparum/parasitología , Plasmodium falciparum/genética , Proteínas Protozoarias/genética , Animales , Anopheles/parasitología , Antimaláricos/farmacología , Antimaláricos/uso terapéutico , Artemisininas/farmacología , Artemisininas/uso terapéutico , Mapeo Cromosómico , Modelos Animales de Enfermedad , Resistencia a Medicamentos/genética , Femenino , Frecuencia de los Genes , Sitios Genéticos , Humanos , Malaria Falciparum/tratamiento farmacológico , Masculino , Ratones , Mosquitos Vectores/parasitología , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , Plasmodium falciparum/efectos de los fármacos , Plasmodium falciparum/crecimiento & desarrollo , Polimorfismo de Nucleótido Simple , Proteínas Ribosómicas/genética , Selección Genética , Quimera por Trasplante
15.
Toxicol Pathol ; 47(8): 976-992, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31610749

RESUMEN

Epidemiological studies report associations between air pollution (AP) exposures and several neurodevelopmental disorders including autism, attention deficit disorder, and cognitive delays. Our studies in mice of postnatal (human third trimester brain equivalent) exposures to concentrated ambient ultrafine particles (CAPs) provide biological plausibility for these associations, producing numerous neuropathological and behavioral features of these disorders, including male-biased vulnerability. These findings raise questions about the specific components of AP that underlie its neurotoxicity, which our studies suggest could involve trace elements as candidate neurotoxicants. X-ray fluorescence analyses of CAP chamber filters confirm contamination of AP exposures by multiple elements, including iron (Fe) and sulfur (S). Correspondingly, laser ablation inductively coupled plasma mass spectrometry of brains of male mice indicates marked postexposure elevations of Fe and S and other elements. Elevations of brain Fe and S in particular are consistent with potential ferroptotic, oxidative stress, and altered antioxidant capacity-based mechanisms of CAPs-induced neurotoxicity, supported by observations of increased serum oxidized glutathione and increased neuronal cell death in nucleus accumbens with no corresponding significant increase in caspase-3, in male brains following postnatal CAP exposures. Understanding the role of trace element contaminants of particulate matter AP as a source of neurotoxicity is critical for public health protection.


Asunto(s)
Contaminantes Atmosféricos/toxicidad , Encéfalo/efectos de los fármacos , Exposición por Inhalación/efectos adversos , Material Particulado/toxicidad , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Contaminantes Atmosféricos/química , Animales , Animales Recién Nacidos , Encéfalo/crecimiento & desarrollo , Encéfalo/metabolismo , Encéfalo/patología , Relación Dosis-Respuesta a Droga , Femenino , Masculino , Ratones Endogámicos C3H , Material Particulado/química , Embarazo , Caracteres Sexuales
16.
Mov Disord Clin Pract ; 6(6): 470-478, 2019 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-31392248

RESUMEN

Background: We have observed in the clinic that a number of patients with Parkinson's disease (PD) can suppress their tremor at will for brief periods, by conscious mental processes. To our knowledge, the ability to consciously diminish one's resting tremor has not yet been reported nor assessed quantitatively. Objective: To provide the first detailed systematic investigation of the phenomenon of voluntary tremor suppression in PD. Methods: We examined changes in tremor characteristics during voluntary tremor suppression in 37 PD patients (on medication) presenting with rest tremor in their upper limb. We measured tremor oscillations with a triaxis accelerometer on the index finger of the most-affected hand (n = 27). With surface electromyography (EMG), we measured changes in neuromuscular activity of the forearm flexor digitorum superficialis and extensor digitorum muscles (n = 15). Participants completed four 1-minute trials, consisting of alternating consecutive 30-second periods of resting tremor and 30-second periods of attempted tremor suppression. Results: Bayesian multilevel modeling revealed that attempted voluntary tremor suppression did indeed reduce tremor amplitude (peak power) of the acceleration signal and increased tremor frequency of the acceleration and EMG signals. Relative EMG power in the 3- to 8-Hz tremor band was also smaller. Tremor suppression was not by enhanced voluntary contraction of the relevant muscle pairs. Conclusions: We present novel empirical evidence that PD resting tremor can be suppressed by an act of will, as evidenced by significant modulation of key neurophysiological tremor characteristics. These data highlight that it is possible to exert significant conscious control over parkinsonian resting tremor.

17.
Genome Med ; 11(1): 54, 2019 08 23.
Artículo en Inglés | MEDLINE | ID: mdl-31443728

RESUMEN

BACKGROUND: DNA methylation changes with age. Chronological age predictors built from DNA methylation are termed 'epigenetic clocks'. The deviation of predicted age from the actual age ('age acceleration residual', AAR) has been reported to be associated with death. However, it is currently unclear how a better prediction of chronological age affects such association. METHODS: In this study, we build multiple predictors based on training DNA methylation samples selected from 13,661 samples (13,402 from blood and 259 from saliva). We use the Lothian Birth Cohorts of 1921 (LBC1921) and 1936 (LBC1936) to examine whether the association between AAR (from these predictors) and death is affected by (1) improving prediction accuracy of an age predictor as its training sample size increases (from 335 to 12,710) and (2) additionally correcting for confounders (i.e., cellular compositions). In addition, we investigated the performance of our predictor in non-blood tissues. RESULTS: We found that in principle, a near-perfect age predictor could be developed when the training sample size is sufficiently large. The association between AAR and mortality attenuates as prediction accuracy increases. AAR from our best predictor (based on Elastic Net, https://github.com/qzhang314/DNAm-based-age-predictor ) exhibits no association with mortality in both LBC1921 (hazard ratio = 1.08, 95% CI 0.91-1.27) and LBC1936 (hazard ratio = 1.00, 95% CI 0.79-1.28). Predictors based on small sample size are prone to confounding by cellular compositions relative to those from large sample size. We observed comparable performance of our predictor in non-blood tissues with a multi-tissue-based predictor. CONCLUSIONS: This study indicates that the epigenetic clock can be improved by increasing the training sample size and that its association with mortality attenuates with increased prediction of chronological age.


Asunto(s)
Envejecimiento/genética , Metilación de ADN , Epigénesis Genética , Epigenómica/métodos , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Humanos , Especificidad de Órganos/genética , Modelos de Riesgos Proporcionales , Reproducibilidad de los Resultados , Saliva
18.
Genome Biol Evol ; 11(7): 1971-1985, 2019 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-31273388

RESUMEN

Malaria parasites have small extremely AT-rich genomes: microsatellite repeats (1-9 bp) comprise 11% of the genome and genetic variation in natural populations is dominated by repeat changes in microsatellites rather than point mutations. This experiment was designed to quantify microsatellite mutation patterns in Plasmodium falciparum. We established 31 parasite cultures derived from a single parasite cell and maintained these for 114-267 days with frequent reductions to a single cell, so parasites accumulated mutations during ∼13,207 cell divisions. We Illumina sequenced the genomes of both progenitor and end-point mutation accumulation (MA) parasite lines in duplicate to validate stringent calling parameters. Microsatellite calls were 99.89% (GATK), 99.99% (freeBayes), and 99.96% (HipSTR) concordant in duplicate sequence runs from independent sequence libraries, whereas introduction of microsatellite mutations into the reference genome revealed a low false negative calling rate (0.68%). We observed 98 microsatellite mutations. We highlight several conclusions: microsatellite mutation rates (3.12 × 10-7 to 2.16 × 10-8/cell division) are associated with both repeat number and repeat motif like other organisms studied. However, 41% of changes resulted from loss or gain of more than one repeat: this was particularly true for long repeat arrays. Unlike other eukaryotes, we found no insertions or deletions that were not associated with repeats or homology regions. Overall, microsatellite mutation rates are among the lowest recorded and comparable to those in another AT-rich protozoan (Dictyostelium). However, a single infection (>1011 parasites) will still contain over 2.16 × 103 to 3.12 × 104 independent mutations at any single microsatellite locus.


Asunto(s)
Malaria/parasitología , Repeticiones de Microsatélite/genética , Parásitos/genética , Animales , Mutación/genética , Acumulación de Mutaciones , Tasa de Mutación
20.
Front Neurol ; 10: 391, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31105633

RESUMEN

The extent to which Alzheimer neuropathology, particularly the accumulation of misfolded beta-amyloid, contributes to cognitive decline and dementia in Parkinson's disease (PD) is unresolved. Here, we used Florbetaben PET imaging to test for any association between cerebral amyloid deposition and cognitive impairment in PD, in a sample enriched for cases with mild cognitive impairment. This cross-sectional study used Movement Disorders Society level II criteria to classify 115 participants with PD as having normal cognition (PDN, n = 23), mild cognitive impairment (PD-MCI, n = 76), or dementia (PDD, n = 16). We acquired 18F-Florbetaben (FBB) amyloid PET and structural MRI. Amyloid deposition was assessed between the three cognitive groups, and also across the whole sample using continuous measures of both global cognitive status and average performance in memory domain tests. Outcomes were cortical FBB uptake, expressed in centiloids and as standardized uptake value ratios (SUVR) using the Centiloid Project whole cerebellum region as a reference, and regional SUVR measurements. FBB binding was higher in PDD, but this difference did not survive adjustment for the older age of the PDD group. We established a suitable centiloid cut-off for amyloid positivity in Parkinson's disease (31.3), but there was no association of FBB binding with global cognitive or memory scores. The failure to find an association between PET amyloid deposition and cognitive impairment in a moderately large sample, particularly given that it was enriched with PD-MCI patients at risk of dementia, suggests that amyloid pathology is not the primary driver of cognitive impairment and dementia in most patients with PD.

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