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Our nearest neighbor, Proxima Centauri, hosts a temperate terrestrial planet. We detected in radial velocities evidence of a possible second planet with minimum mass m c sin i c = 5.8 ± 1.9M â and orbital period P c = 5.21 - 0.22 + 0.26 years. The analysis of photometric data and spectro-scopic activity diagnostics does not explain the signal in terms of a stellar activity cycle, but follow-up is required in the coming years for confirming its planetary origin. We show that the existence of the planet can be ascertained, and its true mass can be determined with high accuracy, by combining Gaia astrometry and radial velocities. Proxima c could become a prime target for follow-up and characterization with next-generation direct imaging instrumentation due to the large maximum angular separation of ~1 arc second from the parent star. The candidate planet represents a challenge for the models of super-Earth formation and evolution.
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OBJECTIVES: Genetic variation of the fat mass and obesity associated gene (FTO) has been identified as a risk factor for obesity and obesity traits. Distribution of FTO single nutleotide polymorphisms (SNPs) rs1421085T>C, rs9939609T>A, rs8057044G>A and copy number variation (CNV) was evaluated in association with childhood obesity or overweight status in children with Mayan ethnicity. METHODS: We included 318 school-aged children with obesity or overweight status (body mass index [BMI]: >85th percentile) and 303 children with normal weight (BMI: 15th-85th percentile). Genotyping was performed using real-time polymerase chain reaction (RT-PCR) with TaqMan probes. The cross-sectional study was carried out using univariate and multivariate logistic regression models adjusted for gender. RESULTS: FTO-SNP rs1421085 showed significant differences between children with obesity and children with normal weight for the heterozygous genotype (P = 0.003) and for allele frequencies (P = 0.023). Adjusting by gender, significant differences were found in frequencies of the hetezygous genotype of SNPs rs9939609 (P = 0.023) and rs1421085 (P = 0.003) as well as in allele frequencies (P = 0.042 and P = 0.013, respectively) between girls with obesity and girls without obesity. In contrast, SNP rs8057044 was significantly different only between heterozygous overweight versus normal weight boys (P = 0.035) and for the allele frequency of rs8057044 (P = 0.021). The mean relative CNV was significantly higher in male overweight children than in boys with normal weight (P = 0.000). CONCLUSIONS: The FTO SNP rs1421085 is a genetic factor associated with obesity in Mayan school-aged children. FTO SNPs rs1421085 and rs9939609 affect genetic susceptibility for obesity only in girls, whereas, SNP rs8057044 and CNV are associated with overweight status only in boys.
Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Peso Corporal/genética , Variação Genética , Sobrepeso/epidemiologia , Adolescente , Criança , Pré-Escolar , Estudos Transversais , Feminino , Humanos , Indígenas Norte-Americanos/estatística & dados numéricos , Masculino , México/epidemiologia , Sobrepeso/genética , Obesidade Infantil/epidemiologia , Obesidade Infantil/genética , Polimorfismo de Nucleotídeo Único , Fatores de RiscoRESUMO
Pain is associated with negative emotions such as anxiety, but the underlying neurocircuitry and modulators of the association of pain and anxiety remain unclear. The neuropeptide cholecystokinin (CCK) has both pronociceptive and anxiogenic properties, so we explored the role of CCK in anxiety and nociception in the central amygdala (CeA), a key area in control of emotions and descending pain pathways. Local infusion of CCK into the CeA of control rats increased anxiety, as measured in the light-dark box test, but had no effect on mechanical sensitivity. By contrast, intra-CeA CCK infusion 4 days after Complete Freund's Adjuvant (CFA) injection into the hindpaw resulted in analgesia, but also in loss of its anxiogenic capacity. Inflammatory conditions induced changes in the CeA CCK signaling system with an increase of CCK immunoreactivity and a decrease in CCK1, but not CCK2, receptor mRNA. In CFA rats, patch-clamp experiments revealed that CCK infusion increased CeA neuron excitability. It also partially blocked the discharge of wide dynamic range neurons in the dorsal spinal cord. These effects of CCK on CeA and spinal neurons in CFA rats were mimicked by the specific CCK2 receptor agonist, gastrin. This analgesic effect was likely mediated by identified CeA neurons projecting to the periaqueductal gray matter that express CCK receptors. Together, our data demonstrate that intra-CeA CCK infusion activated a descending CCK2 receptor-dependent pathway that inhibited spinal neuron discharge. Thus, persistent pain induces a functional switch to a newly identified analgesic capacity of CCK in the amygdala, indicating central emotion-related circuit controls pain transmission in spinal cord.
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Tonsila do Cerebelo/metabolismo , Colecistocinina/metabolismo , Dor/patologia , Receptor de Colecistocinina B/metabolismo , Transdução de Sinais/fisiologia , Tonsila do Cerebelo/patologia , Animais , Adaptação à Escuridão/efeitos dos fármacos , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Adjuvante de Freund/toxicidade , Gastrinas/uso terapêutico , Glutamato Descarboxilase/metabolismo , Inflamação/induzido quimicamente , Inflamação/complicações , Masculino , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Nociceptividade/efeitos dos fármacos , Dor/etiologia , Limiar da Dor/efeitos dos fármacos , Substância Cinzenta Periaquedutal/efeitos dos fármacos , Substância Cinzenta Periaquedutal/fisiologia , Ratos , Ratos Sprague-Dawley , Receptor de Colecistocinina B/agonistas , Receptor de Colecistocinina B/antagonistas & inibidores , Receptor de Colecistocinina B/genética , Transdução de Sinais/efeitos dos fármacos , Sincalida/uso terapêutico , Tetragastrina/análogos & derivados , Tetragastrina/uso terapêuticoRESUMO
In the central nervous system (CNS), miRNAs are involved in key functions, such as neurogenesis and synaptic plasticity. Moreover, they are essential to define specific transcriptomes in tissues and cells. However, few studies were performed to determine the miRNome of the different structures of the rat CNS, although a major model in neuroscience. Here, we determined by small RNA-Seq, the miRNome of the olfactory bulb, the hippocampus, the cortex, the striatum, and the spinal cord and showed the expression of 365 known miRNAs and 90 novel miRNAs. Differential expression analysis showed that several miRNAs were specifically enriched/depleted in these CNS structures. Transcriptome analysis by mRNA-Seq and correlation based on miRNA target predictions suggest that the specifically enriched/depleted miRNAs have a strong impact on the transcriptomic identity of the CNS structures. Altogether, these results suggest the critical role played by these enriched/depleted miRNAs, in particular the novel miRNAs, in the functional identities of CNS structures.
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Oxaliplatin is a platinum-based drug used in the treatment of gastric cancers. Oxaliplatin treatment induces sensory neuropathy characterized by cold hypersensibility in the acute phase and sensory impairment when the neuropathy becomes chronic. In order to determine the effect of oxaliplatin on sensory neurons, we used an in vitro model in which oxaliplatin treatment reduced arborization of dorsal root ganglia neurons in a dose-dependent manner. Moreover, we characterized the role of microRNAs in oxaliplatin induced-neuropathy. In particular, we focused on microRNAs that control the expression of axon guidance molecules, and therefore, regulate neurite arborization. As a result, we highlighted the upregulation of miR-204, a microRNA that controls the expression of PlexinA2, a semaphorin receptor involved in neurite guidance. Interaction of miR-204 and Plexin A2 was confirmed by luciferase assay. In addition, overexpression of miR-204 in dorsal root ganglia neuron cultures reduced length and extension of neurites and also reduced Plexin A2 labelling without increasing apoptosis rate. On the other hand, sequestration of miR-204 by a specific microRNA sponge increases neurite length and PlexinA2 expression. Taken together, our data indicate that oxaliplatin impairs sensory neurons arborization through up-regulation of miR-204 that decreases PlexinA2 expression and neurite length.
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MicroRNAs/metabolismo , Neuritos/efeitos dos fármacos , Neuritos/metabolismo , Oxaliplatina/farmacologia , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo , Animais , Orientação de Axônios/efeitos dos fármacos , Feminino , Gânglios Espinais/efeitos dos fármacos , Gânglios Espinais/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/metabolismo , Cultura Primária de Células , Receptores de Superfície Celular/metabolismoRESUMO
Abstract: The dorsal horn of the spinal cord is a crucial site for pain transmission and modulation. Dorsal horn neurons of the spinal cord express group I metabotropic glutamate receptors (group I mGluRs) that exert a complex role in nociceptive transmission. In particular, group I mGluRs promote the activation of L-type calcium channels, voltage-gated channels involved in short- and long-term sensitization to pain. In this study, we analyzed the role of group I mGluRs in spinal nociceptive transmission and the possible cooperation between these receptors and L-type calcium channels in the pathophysiology of pain transmission in the dorsal horn of the spinal cord. We demonstrate that the activation of group I mGluRs induces allodynia and L-type calcium channel-dependent increase in nociceptive field potentials following sciatic nerve stimulation. Surprisingly, in a model of persistent inflammation induced by complete Freund's adjuvant, the activation of group I mGluRs induced an analgesia and a decrease in nociceptive field potentials. Among the group I mGluRs, mGluR1 promotes the activation of L-type calcium channels and increased nociceptive transmission while mGluR5 induces the opposite through the inhibitory network. These results suggest a functional switch exists in pathological conditions that can change the action of group I mGluR agonists into possible analgesic molecules, thereby suggesting new therapeutic perspectives to treat persistent pain in inflammatory settings.
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Hiperalgesia/fisiopatologia , Inflamação/metabolismo , Plasticidade Neuronal/fisiologia , Receptores de Glutamato Metabotrópico/metabolismo , Animais , Masculino , Células do Corno Posterior/metabolismo , Ratos Sprague-Dawley , Receptores de Glutamato Metabotrópico/análise , Medula Espinal/fisiologia , Sinapses/metabolismoRESUMO
Strong breakthrough pain is one of the most disabling symptoms of cancer since it affects up to 90% of cancer patients and is often refractory to treatments. Alteration in gene expression is a known mechanism of cancer pain in which microRNAs (miRNAs), a class of non-coding regulatory RNAs, play a crucial role. Here, in a mouse model of cancer pain, we show that miR-124 is down-regulated in the spinal cord, the first relay of the pain signal to the brain. Using in vitro and in vivo approaches, we demonstrate that miR-124 is an endogenous and specific inhibitor of synaptopodin (Synpo), a key protein for synaptic transmission. In addition, we demonstrate that Synpo is a key component of the nociceptive pathways. Interestingly, miR-124 was down-regulated in the spinal cord in cancer pain conditions, leading to an up-regulation of Synpo. Furthermore, intrathecal injections of miR-124 mimics in cancerous mice normalized Synpo expression and completely alleviated cancer pain in the early phase of the cancer. Finally, miR-124 was also down-regulated in the cerebrospinal fluid of cancer patients who developed pain, suggesting that miR-124 could be an efficient analgesic drug to treat cancer pain patients.
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Neoplasias Ósseas/fisiopatologia , Dor do Câncer/metabolismo , MicroRNAs/genética , Nociceptividade , Medula Espinal/metabolismo , Animais , Neoplasias Ósseas/complicações , Dor do Câncer/etiologia , Humanos , Masculino , Camundongos , MicroRNAs/metabolismo , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismoRESUMO
Chronic pain is a major public health issue with an incidence of 20-25% worldwide that can take different forms like neuropathic, cancer-related or inflammatory pain. Chronic pain often limits patients in their daily activities leading to despair. Thus, the goal of treatments is to relieve pain sufficiently to enable patients to go back to a normal life. Unfortunately, few patients with chronic pain obtain complete relief from the analgesics that are currently available. It is thus of prime importance to get a better understanding of chronic pain mechanisms to design new therapeutic strategies and pain-killers. In this sense, the study of microRNA (miRNAs) in chronic pain conditions could lead to a breakthrough in pain management. miRNAs have emerged as master regulators of gene expression in the nervous system where they contribute to neuronal network plasticity. The involvement of miRNAs in the maladaptive plasticity mechanisms of chronic pain is now well documented. Here, we review studies conducted in different animal models and in patients that screened chronic pain-related miRNAs and their targets. Clinical studies suggest that miRNAs expression could reflect the high variability among pain patients that could help to categorize patients and finally lead to personalized therapies. We also point out the different strategies investigated to design miRNA-based analgesics. Finally, we highlight the current miRNA-based clinical trials to hypothesize their potential as therapeutic tool for chronic pain.
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Dor Crônica/tratamento farmacológico , Dor Crônica/genética , MicroRNAs , Animais , HumanosRESUMO
Mutations in the GBA1 gene encoding the lysosomal enzyme glucocerebrosidase (GBA1) are important risk factors for Parkinson's disease (PD). In vitro, altered GBA1 activity promotes alpha-synuclein accumulation whereas elevated levels of alpha-synuclein compromise GBA1 function, thus supporting a pathogenic mechanism in PD. However, the mechanisms by which GBA1 deficiency is linked to increased risk of PD remain elusive, partially because of lack of aged models of GBA1 deficiency. As knocking-out GBA1 in the entire brain induces massive neurodegeneration and early death, we generated a mouse model of GBA1 deficiency amenable to investigate the long-term consequences of compromised GBA1 function in dopaminergic neurons. DAT-Cre and GBA1-floxed mice were bred to obtain selective homozygous disruption of GBA1 in midbrain dopamine neurons (DAT-GBA1-KO). Mice were followed for motor function, neuronal survival, alpha-synuclein phosphorylation and glial activation. Susceptibility to nigral viral vector-mediated overexpression of mutated (A53T) alpha-synuclein was assessed. Despite loss of GBA1 and substrate accumulation, DAT-GBA1-KO mice displayed normal motor performances and preserved dopaminergic neurons despite robust microglial activation in the substantia nigra, without accumulation of endogenous alpha-synuclein with respect to wild-type mice. Lysosomal function was only marginally affected. Screening of micro-RNAs linked to the regulation of GBA1, alpha-synuclein or neuroinflammation did not reveal significant alterations. Viral-mediated overexpression of A53T-alpha-synuclein yielded similar neurodegeneration in DAT-GBA1-KO mice and wild-type mice. These results indicate that loss of GBA1 function in mouse dopaminergic neurons is not critical for alpha-synuclein accumulation or neurodegeneration and suggest the involvement of GBA1 deficiency in other cell types as a potential mechanism.
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Neurônios Dopaminérgicos/metabolismo , Glucosilceramidase/genética , Glucosilceramidase/metabolismo , Animais , Encéfalo/metabolismo , Doença de Gaucher/genética , Doença de Gaucher/metabolismo , Vetores Genéticos , Mesencéfalo/metabolismo , Camundongos , Camundongos Knockout , Microglia/metabolismo , Modelos Animais , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , Substância Negra/metabolismo , alfa-Sinucleína/metabolismoRESUMO
KEY POINTS: L-type calcium channels in the CNS exist as two subunit forming channels, Cav1.2 and Cav1.3, which are involved in short- and long-term plasticity. We demonstrate that Cav1.3 but not Cav1.2 is essential for wind-up. These results identify Cav1.3 as a key conductance responsible for short-term sensitization in physiological pain transmission. We confirm the role of Cav1.2 in a model of long-term plasticity associated with neuropathic pain. Up-regulation of Cav1.2 and down-regultation of Cav1.3 in neuropathic pain underlies the switch from physiology to pathology. Finally, the results of the present study reveal that therapeutic targeting molecular pathways involved in wind-up may be not relevant in the treatment of neuropathy. ABSTRACT: Short-term central sensitization to pain temporarily increases the responsiveness of nociceptive pathways after peripheral injury. In dorsal horn neurons (DHNs), short-term sensitization can be monitored through the study of wind-up. Wind-up, a progressive increase in DHNs response following repetitive peripheral stimulations, depends on the post-synaptic L-type calcium channels. In the dorsal horn of the spinal cord, two L-type calcium channels are present, Cav1.2 and Cav1.3, each displaying specific kinetics and spatial distribution. In the present study, we used a mathematical model of DHNs in which we integrated the specific patterns of expression of each Cav subunits. This mathematical approach reveals that Cav1.3 is necessary for the onset of wind-up, whereas Cav1.2 is not and that synaptically triggered wind-up requires NMDA receptor activation. We then switched to a biological preparation in which we knocked down Cav subunits and confirmed the prominent role of Cav1.3 in both naive and spinal nerve ligation model of neuropathy (SNL). Interestingly, although a clear mechanical allodynia dependent on Cav1.2 expression was observed after SNL, the amplitude of wind-up was decreased. These results were confirmed with our model when adapting Cav1.3 conductance to the changes observed after SNL. Finally, our mathematical approach predicts that, although wind-up amplitude is decreased in SNL, plateau potentials are not altered, suggesting that plateau and wind-up are not fully equivalent. Wind-up and long-term hyperexcitability of DHNs are differentially controlled by Cav1.2 and Cav1.3, therefore confirming that short- and long-term sensitization are two different phenomena triggered by distinct mechanisms.
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Canais de Cálcio Tipo L/metabolismo , Canais de Cálcio/metabolismo , Neuralgia/metabolismo , Potenciais de Ação/fisiologia , Animais , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatologia , Masculino , Neuralgia/fisiopatologia , Ratos , Ratos Wistar , Receptores de N-Metil-D-Aspartato/metabolismo , Medula Espinal/metabolismo , Medula Espinal/fisiopatologia , Corno Dorsal da Medula Espinal/metabolismo , Corno Dorsal da Medula Espinal/fisiopatologia , Nervos Espinhais/metabolismo , Nervos Espinhais/fisiopatologia , Sinapses/metabolismoRESUMO
The spectral airglow temperature imager is a two-channel, Fabry-Perot spectrometer with an annular field of view and a cooled CCD detector. The detected fringe pattern contains spectral information in the radial direction and azimuthal spatial information from the annular field of view. The instrument measures the rotational temperature from the O2 atmospheric (0,1) nightglow emission layer at 94 km and from the Q branch of the OH Meinel (6,2) band emission layer at 87 km. The method for temperature derivation is based on the temperature dependence of the line-emission rates. This dependence allows a determination of the temperature by a least-squares fit of the measured spectrum to a set of synthetic spectra, an approach that minimizes the effect of noise from the sky background and the detector. The spectral airglow temperature imager was developed to meet a need for monitoring the role of the mesosphere in climate variability through long-term observation of the mean temperature and the gravity waves from a single station, as well as large-scale wave perturbations through the use of multiple stations.