RESUMO
Phantom tooth pain (PTP) is one type of non-odontogenic neuropathic toothache, which rarely occurs after appropriate pulpectomy or tooth extraction. The cause of PTP is unknown. We investigated pain-related genetic factors that are associated with PTP. Four pain-associated genes, including G protein-coupled receptor 158 (GPR158) and phosphoribosyl transferase domain containing 1 (PRTFDC1), are adjacent to each other on the human genome. Some of these four genes or their genomic region may be related to PTP. We statistically analyzed associations between single-nucleotide polymorphisms (SNPs) in the genomic region and PTP in patients with PTP (PTP group), other orofacial pain (OFP group), and healthy control subjects. We then performed a database search of expression quantitative trait loci (eQTLs). For the seven SNPs that were significantly associated with PTP even after Bonferroni correction, we focused on the rs12411980 tag SNP (P = 9.42 × 10-4). Statistical analyses of the PTP group and healthy subject groups (group labels: NOC and TD) revealed that the rate of the GG genotype of the rs12411980 SNP was significantly higher in the PTP group than in the healthy subject groups (PTP group vs. NOC group: P = 2.92 × 10-4, PTP group vs. TD group: P = 5.46 × 10-4; percentage of GG: 30% in PTP group, 12% in NOC group, 11% in TD group). These results suggest that the GG genotype of the rs12411980 SNP is more susceptible to PTP. The rs2765697 SNP that is in strong linkage disequilibrium with the rs12411980 SNP is an eQTL that is associated with higher PRTFDC1 expression in the minor allele homozygotes in the healthy subject groups of the rs2765697 SNP. Thus, PRTFDC1 expression similarly increases in the minor allele homozygotes (GG genotype) in the healthy subject groups of the rs12411980 SNP, which would lead to greater susceptibility to PTP.
RESUMO
Phantom tooth pain (PTP) is a rare and specific neuropathic pain that occurs after pulpectomy and tooth extraction, but its cause is not understood. We hypothesized that there is a genetic contribution to PTP. The present study focused on the CACNA1C gene, which encodes the α1C subunit of the Cav1.2 L-type Ca2+ channel (LTCC) that has been reported to be associated with neuropathic pain in previous studies. We investigated genetic polymorphisms that contribute to PTP. We statistically examined the association between genetic polymorphisms and PTP vulnerability in 33 patients with PTP and 118 patients without PTP but with pain or dysesthesia in the orofacial region. From within and around the CACNA1C gene, 155 polymorphisms were selected and analyzed for associations with clinical data. We found that the rs216009 single-nucleotide polymorphism (SNP) of the CACNA1C gene in the recessive model was significantly associated with the vulnerability to PTP. Homozygote carriers of the minor C allele of rs216009 had a higher rate of PTP. Nociceptive transmission in neuropathic pain has been reported to involve Ca2+ influx from LTCCs, and the rs216009 polymorphism may be involved in CACNA1C expression, which regulates intracellular Ca2+ levels, leading to the vulnerability to PTP. Furthermore, psychological factors may lead to the development of PTP by modulating the descending pain inhibitory system. Altogether, homozygous C-allele carriers of the rs216009 SNP were more likely to be vulnerable to PTP, possibly through the regulation of intracellular Ca2+ levels and affective pain systems, such as those that mediate fear memory recall.
Assuntos
Neuralgia , Polimorfismo de Nucleotídeo Único , Humanos , Polimorfismo de Nucleotídeo Único/genética , Canais de Cálcio Tipo L/genética , Canais de Cálcio Tipo L/metabolismo , Neuralgia/genéticaRESUMO
BACKGROUND: Individuals with schizophrenia (SCZ) and bipolar disorder (BD) display cognitive impairments, but the impairments in those with SCZ are more prominent, supported by genetic overlap between SCZ and cognitive impairments. However, it remains unclear whether cognitive performances differ between individuals at high and low genetic risks for SCZ or BD. METHODS: Using the latest Psychiatric Genomics Consortium (PGC) data, we calculated PGC3 SCZ-, PGC3 BD-, and SCZ v. BD polygenic risk scores (PRSs) in 173 SCZ patients, 70 unaffected first-degree relatives (FRs) and 196 healthy controls (HCs). Based on combinations of three PRS deciles, individuals in the genetic SCZ, genetic BD and low genetic risk groups were extracted. Cognitive performance was assessed by the Brief Assessment of Cognition in Schizophrenia. RESULTS: SCZ-, BD-, SCZ v. BD-PRSs were associated with case-control status (R2 = 0.020-0.061), and SCZ-PRS was associated with relative-control status (R2 = 0.023). Furthermore, individuals in the highest decile for SCZ PRSs had elevated BD-PRSs [odds ratio (OR) = 6.33] and SCZ v. BD-PRSs (OR = 1.86) compared with those in the lowest decile. Of the three genetic risk groups, the low genetic risk group contained more HCs, whereas the genetic BD and SCZ groups contained more SCZ patients (p < 0.05). SCZ patients had widespread cognitive impairments, and FRs had cognitive impairments that were between those of SCZ patients and HCs (p < 0.05). Cognitive differences between HCs in the low genetic risk group and SCZ patients in the genetic BD or genetic SCZ groups were more prominent (Cohen's d > -0.20) than those between HCs and SCZ patients in the no genetic risk group. Furthermore, SCZ patients in the genetic SCZ group displayed lower scores in verbal fluency and attention than those in the genetic BD group (d > -0.20). CONCLUSIONS: Our findings suggest that cognitive impairments in SCZ are partially mediated through genetic loadings for SCZ but not BD.
Assuntos
Transtorno Bipolar , Disfunção Cognitiva , Esquizofrenia , Humanos , Transtorno Bipolar/genética , Transtorno Bipolar/psicologia , Esquizofrenia/genética , Fatores de Risco , Disfunção Cognitiva/genética , Cognição , Herança Multifatorial , Predisposição Genética para DoençaRESUMO
Sensitivity to opioids varies widely among individuals. To identify potential candidate single-nucleotide polymorphisms (SNPs) that may significantly contribute to individual differences in the minimum effective concentration (MEC) of an opioid, fentanyl, we conducted a three-stage genome-wide association study (GWAS) using whole-genome genotyping arrays in 350 patients who underwent laparoscopic-assisted colectomy. To estimate the MEC of fentanyl, plasma and effect-site concentrations of fentanyl over the 24 h postoperative period were estimated with a pharmacokinetic simulation model based on initial bolus doses and subsequent patient-controlled analgesia doses of fentanyl. Plasma and effect-site MECs of fentanyl were indicated by fentanyl concentrations, estimated immediately before each patient-controlled analgesia dose. The GWAS revealed that an intergenic SNP, rs966775, that mapped to 5p13 had significant associations with the plasma MEC averaged over the 6 h postoperative period and the effect-site MEC averaged over the 12 h postoperative period. The minor G allele of rs966775 was associated with increases in these MECs of fentanyl. The nearest protein-coding gene around this SNP was DRD1, encoding the dopamine D1 receptor. In the gene-based analysis, the association was significant for the SERP2 gene in the dominant model. Our findings provide valuable information for personalized pain treatment after laparoscopic-assisted colectomy.
Assuntos
Fentanila , Laparoscopia , Humanos , Estudo de Associação Genômica Ampla , Dor Pós-Operatória/etiologia , Dor Pós-Operatória/genética , Analgésicos Opioides/uso terapêutico , Polimorfismo de Nucleotídeo Único , ColectomiaRESUMO
Chronic pain is reportedly associated with the transient receptor potential canonical 3 (TRPC3) gene. The present study examined the genetic associations between the single-nucleotide polymorphisms (SNPs) of the TRPC3 gene and chronic pain. The genomic samples from 194 patients underwent linkage disequilibrium (LD) analyses of 29 SNPs within and around the vicinity of the TRPC3 gene. We examined the associations between the SNPs and the susceptibility to chronic pain by comparing the genotype distribution of 194 patients with 282 control subjects. All SNP genotype data were extracted from our previous whole-genome genotyping results. Twenty-nine SNPs were extracted, and a total of four LD blocks with 15 tag SNPs were observed within and around the TRPC3 gene. We further analyzed the associations between these tag SNPs and chronic pain. The rs11726196 SNP genotype distribution of patients was significantly different from the control subjects even after multiple-testing correction with the number of SNPs. The TT + TG genotype of rs11726196 is often carried by chronic pain patients, suggesting a causal role for the T allele. These results contribute to our understanding of the genetic risk factors for chronic pain.
Assuntos
Dor Crônica , Polimorfismo de Nucleotídeo Único , Canais de Cátion TRPC , Humanos , Dor Crônica/genética , Ligação Genética , Predisposição Genética para Doença , Genótipo , Desequilíbrio de Ligação , Canais de Cátion TRPC/genéticaRESUMO
Patients with chronic pain are affected psychologically and socially. There are also individual differences in treatment efficacy. Insufficient research has been conducted on genetic polymorphisms that are related to individual differences in the susceptibility to chronic pain. Autoimmune disorders can lead to inflammation and chronic pain; therefore, we focused on the autoimmune-related protease-activated receptor 2 (PAR2/F2RL1) and interleukin 17A (IL-17A/IL17A) genes. PAR2 and IL-17A are associated with autoimmune diseases that lead to chronic pain, and PAR2 regulates T-helper (Th) cell activation and differentiation. We hypothesized that the PAR2 and IL-17A genes are associated with chronic pain. The present study used a case-control design to statistically examine associations between genetic polymorphisms and the vulnerability to chronic pain. The rs2243057 polymorphism of the PAR2 gene and rs3819025 polymorphism of the IL-17A gene were previously reported to be associated with pain- or autoimmune-related phenotypes. Thus, these polymorphisms were investigated in the present study. We found that both rs2243057 and rs3819025 were significantly associated with a susceptibility to chronic pain. The present findings revealed autoimmune-related genetic factors that are involved in individual differences in chronic pain, further aiding understanding of the pathomechanism that underlies chronic pain and possibly contributing to future personalized medicine.
Assuntos
Doenças Autoimunes , Dor Crônica , Interleucina-17 , Receptor PAR-2 , Humanos , Estudos de Casos e Controles , Dor Crônica/genética , Predisposição Genética para Doença , Interleucina-17/genética , Polimorfismo de Nucleotídeo Único , Receptor PAR-2/genéticaRESUMO
Phantom tooth pain (PTP) is a rare and specific neuropathic pain that occurs after pulpectomy and tooth extraction, but its cause is not understood. We hypothesized that there is a genetic contribution to PTP. We focused on solute carrier family 17 member 9 (SLC17A9)/vesicular nucleotide transporter (VNUT) and purinergic receptor P2Y12 (P2RY12), both of which have been associated with neuropathic pain and pain transduction signaling in the trigeminal ganglion in rodents. We sought to corroborate these associations in humans. We investigated gene polymorphisms that contribute to PTP. We statistically examined the association between genetic polymorphisms and PTP vulnerability in 150 patients with orofacial pain, including PTP, and 500 healthy subjects. We found that the rs735055 polymorphism of the SLC17A9 gene and rs3732759 polymorphism of the P2RY12 gene were associated with the development of PTP. Carriers of the minor allele of rs735055 and individuals who were homozygous for the major allele of rs3732759 had a higher rate of PTP. Carriers of the minor allele of rs735055 reportedly had high SLC17A9 mRNA expression in the spinal cord, which may increase the storage and release of adenosine triphosphate. Individuals who were homozygous for the major allele of rs3732759 may have higher P2RY12 expression that is more active in microglia. Therefore, these carriers may be more susceptible to PTP. These results suggest that specific genetic polymorphisms of the SLC17A9 and P2RY12 genes are involved in PTP. This is the first report on genes that are associated with PTP in humans.
Assuntos
Neuralgia , Proteínas de Transporte de Nucleotídeos , Humanos , Trifosfato de Adenosina/metabolismo , Proteínas de Transporte de Nucleotídeos/genética , Proteínas de Transporte de Nucleotídeos/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Receptores Purinérgicos P2Y12/genética , Receptores Purinérgicos P2Y12/metabolismoRESUMO
Pain sensitivity differs individually, but the mechanisms and genetic factors that underlie these differences are not fully understood. To investigate genetic factors that are involved in sensing cold pain, we applied a cold-induced pain test and evaluated protease-activated receptor 2 (PAR2/F2RL1) and transient receptor potential melastatin 8 (TRPM8), which are related to pain. We statistically investigated the associations between genetic polymorphisms and cold pain sensitivity in 461 healthy patients who were scheduled to undergo cosmetic orthognathic surgery for mandibular prognathism. We found an association between cold pain sensitivity and the rs2243057 polymorphism of the PAR2 gene. We also found a significant association between cold pain sensitivity and the rs12992084 polymorphism of the TRPM8 gene. Carriers of the minor A allele of the rs2243057 polymorphism of PAR2 and minor C allele of the rs12992084 polymorphism of TRPM8 exhibited a longer latency to pain perception in the cold-induced pain test, reflecting a decrease in cold pain sensitivity. These results suggest that genetic polymorphisms of both PAR2 and TRPM8 are involved in individual differences in cold pain sensitivity.
Assuntos
Temperatura Baixa , Dor/genética , Receptor PAR-2/metabolismo , Canais de Cátion TRPM/metabolismo , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Dor/metabolismo , Dor/fisiopatologia , Percepção da Dor/fisiologia , Limiar da Dor/fisiologia , Receptor PAR-2/genética , Canais de Cátion TRPM/genética , Sensação Térmica/fisiologia , Adulto JovemRESUMO
Acute pain that is associated with herpes zoster (HZ) can become long-lasting neuropathic pain, known as chronic post-herpetic neuralgia (PHN), especially in the elderly. HZ is caused by the reactivation of latent varicella-zoster virus (VZV), whereas PHN is not attributed to ongoing viral replication. Although VZV infection reportedly induces neuronal cell fusion in humans, the pathogenesis of PHN is not fully understood. A genome-wide association study (GWAS) revealed significant associations between PHN and the rs12596324 single-nucleotide polymorphism (SNP) of the heparan sulfate 3-O-sulfotransferase 4 (HS3ST4) gene in a previous study. To further examine whether this SNP is associated with both PHN and VZV reactivation, associations between rs12596324 and a history of HZ were statistically analyzed using GWAS data. HZ was significantly associated with the rs12596324 SNP of HS3ST4, indicating that HS3ST4 is related to viral replication. We investigated the influence of HS3ST4 expression on VZV infection in cultured cells. Fusogenic activity after VZV infection was enhanced in cells with HS3ST4 expression by microscopy. To quantitatively evaluate the fusogenic activity, we applied cytotoxicity assay and revealed that HS3ST4 expression enhanced cytotoxicity after VZV infection. Expression of the VZV glycoproteins gB, gH, and gL significantly increased cytotoxicity in cells with HS3ST4 expression by cytotoxicity assay, consistent with the fusogenic activity as visualized by fluorescence microscopy. HS3ST4 had little influence on viral genome replication, revealed by quantitative real-time polymerase chain reaction. These results suggest that HS3ST4 enhances cytotoxicity including fusogenic activity in the presence of VZV glycoproteins without enhancing viral genome replication.
Assuntos
Herpes Zoster , Neuralgia Pós-Herpética , Sulfotransferases/genética , Estudo de Associação Genômica Ampla , Herpes Zoster/genética , Herpesvirus Humano 3/genética , HumanosRESUMO
BACKGROUND: Human twin studies and other studies have indicated that chronic pain has heritability that ranges from 30% to 70%. We aimed to identify potential genetic variants that contribute to the susceptibility to chronic pain and efficacy of administered drugs. We conducted genome-wide association studies (GWASs) using whole-genome genotyping arrays with more than 700,000 markers in 191 chronic pain patients and a subgroup of 89 patients with postherpetic neuralgia (PHN) in addition to 282 healthy control subjects in several genetic models, followed by additional gene-based and gene-set analyses of the same phenotypes. We also performed a GWAS for the efficacy of drugs for the treatment of pain. RESULTS: Although none of the single-nucleotide polymorphisms (SNPs) were found to be genome-wide significantly associated with chronic pain (p ≥ 1.858 × 10-7), the GWAS of PHN patients revealed that the rs4773840 SNP within the ABCC4 gene region was significantly associated with PHN in the trend model (nominal p = 1.638 × 10-7). In the additional gene-based analysis, one gene, PRKCQ, was significantly associated with chronic pain in the trend model (adjusted p = 0.03722). In the gene-set analysis, several gene sets were significantly associated with chronic pain and PHN. No SNPs were significantly associated with the efficacy of any of types of drugs in any of the genetic models. CONCLUSIONS: These results suggest that the PRKCQ gene and rs4773840 SNP within the ABCC4 gene region may be related to the susceptibility to chronic pain conditions and PHN, respectively.
Assuntos
Dor Crônica/genética , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neuralgia Pós-Herpética/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Adulto JovemRESUMO
BACKGROUND: Impairments in intelligence are more severe in patients with schizophrenia (SCZ) than in patients with bipolar disorder (BD) despite clinical and genetic similarities between the disorders. Genetic loci differentiating SCZ from BD, that is, SCZ-specific risk, have been identified. Polygenetic [risk] scores (PGSs) for SCZ-specific risk are higher in SCZ patients than in healthy controls (HCs). However, the influence of genetic risk on impaired intelligence is poorly understood. Here, we investigated whether SCZ-specific risk could predict impairments in intelligence in SCZ patients and HCs. METHODS: Large-scale genome-wide association study datasets related to SCZ vs BD, childhood intelligence (CHI), and adulthood intelligence (n = 12 441-282â 014) were utilized to compute PGSs. PGSs derived from the genome-wide association studies were calculated for 130 patients with SCZ and 146 HCs. Premorbid and current intelligence and the decline were measured in SCZ patients and HCs. Correlations between PGSs and intelligence functions were investigated. RESULTS: High PGSs for SCZ-specific risk were correlated with low premorbid intelligence in SCZ patients and HCs (ß = -0.17, P = 4.12 × 10-3). The correlation was still significant after adjusting for diagnostic status (ß = -0.13, P = .024). There were no significant correlations between PGSs for SCZ-specific risk and current intelligence or intelligence decline (Pâ >â .05). PGSs for CHI were lower in SCZ patients than in HCs (R2 = 0.025, P = .025), while the PGSs for CHI were not significantly correlated with premorbid and current intelligence, the decline, or the PGSs for SCZ-specific risk (Pâ >â .05). CONCLUSIONS: These findings suggest that genetic factors differentiating SCZ from BD might affect the pathogenesis of SCZ and/or pathological differences between SCZ and BD via the impairment of premorbid intelligence, that is, crystallized intelligence, while genetic factors for CHI might affect the pathogenesis of SCZ but not via impairments in intelligence.
Assuntos
Transtorno Bipolar , Disfunção Cognitiva , Predisposição Genética para Doença , Inteligência/fisiologia , Esquizofrenia , Adulto , Transtorno Bipolar/complicações , Transtorno Bipolar/genética , Transtorno Bipolar/fisiopatologia , Disfunção Cognitiva/etiologia , Disfunção Cognitiva/genética , Disfunção Cognitiva/fisiopatologia , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Esquizofrenia/complicações , Esquizofrenia/genética , Esquizofrenia/fisiopatologia , Adulto JovemRESUMO
BACKGROUND: The genetic etiology of schizophrenia (SCZ) overlaps with that of other major psychiatric disorders in samples of European ancestry. The present study investigated transethnic polygenetic features shared between Japanese SCZ or their unaffected first-degree relatives and European patients with major psychiatric disorders by conducting polygenic risk score (PRS) analyses. METHODS: To calculate PRSs for 5 psychiatric disorders (SCZ, bipolar disorder [BIP], major depressive disorder, autism spectrum disorder, and attention-deficit/hyperactivity disorder) and PRSs differentiating SCZ from BIP, we utilized large-scale European genome-wide association study (GWAS) datasets as discovery samples. PRSs derived from these GWASs were calculated for 335 Japanese target participants [SCZ patients, FRs, and healthy controls (HCs)]. We took these PRSs based on GWASs of European psychiatric disorders and investigated their effect on risk in Japanese SCZ patients and unaffected first-degree relatives. RESULTS: The PRSs obtained from European SCZ and BIP patients were higher in Japanese SCZ patients than in HCs. Furthermore, PRSs differentiating SCZ patients from European BIP patients were higher in Japanese SCZ patients than in HCs. Interestingly, PRSs related to European autism spectrum disorder were lower in Japanese first-degree relatives than in HCs or SCZ patients. The PRSs of autism spectrum disorder were positively correlated with a young onset age of SCZ. CONCLUSIONS: These findings suggest that polygenic factors related to European SCZ and BIP and the polygenic components differentiating SCZ from BIP can transethnically contribute to SCZ risk in Japanese people. Furthermore, we suggest that reduced levels of an ASD-related genetic factor in unaffected first-degree relatives may help protect against SCZ development.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/genética , Transtorno do Espectro Autista/genética , Transtorno Bipolar/genética , Transtorno Depressivo Maior/genética , Predisposição Genética para Doença/genética , Esquizofrenia/genética , Adulto , Filhos Adultos , Transtorno do Deficit de Atenção com Hiperatividade/etnologia , Transtorno do Espectro Autista/etnologia , Transtorno Bipolar/etnologia , Transtorno Depressivo Maior/etnologia , Europa (Continente)/etnologia , Feminino , Predisposição Genética para Doença/etnologia , Estudo de Associação Genômica Ampla , Humanos , Japão/etnologia , Masculino , Pessoa de Meia-Idade , Herança Multifatorial , Pais , Risco , Esquizofrenia/etnologia , IrmãosRESUMO
BACKGROUND: Sodium channels located in the dorsal root ganglion, particularly Nav1.7 and Nav1.8, encoded by SCN9A and SCN10A, respectively, act as molecular gatekeepers for pain detection. Our aim was to determine the association between TIPN and SCN9A and SCN10A polymorphisms. METHODS: Three single nucleotide polymorphisms (SNPs) in SCN9A and two in SCN10A were investigated using whole-genome genotyping data from 186 Japanese breast or ovarian cancer patients classified into two groups as follows: cases that developed taxane-induced grade 2-3 neuropathy (N = 108) and controls (N = 78) with grade 0-1 neuropathy. Multiple logistic regression analyses were conducted to evaluate associations between TIPN and SNP genotypes. RESULTS: SCN9A-rs13017637 was a significant predictor of grade 2 or higher TIPN (odds ratio (OR) = 3.463; P = 0.0050) after correction for multiple comparisons, and precision was improved when only breast cancer patients were included (OR 5.053, P = 0.0029). Moreover, rs13017637 was a significant predictor of grade 2 or higher TIPN 1 year after treatment (OR 3.906, P = 0.037), indicating its contribution to TIPN duration. CONCLUSION: SCN9A rs13017637 was associated with the severity and duration of TIPN. These findings are highly exploratory and require replication and validation prior to any consideration of clinical use.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Canal de Sódio Disparado por Voltagem NAV1.7/genética , Neoplasias Ovarianas/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/patologia , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Ciclofosfamida/administração & dosagem , Docetaxel/administração & dosagem , Doxorrubicina/administração & dosagem , Epirubicina/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Japão/epidemiologia , Pessoa de Meia-Idade , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Paclitaxel/administração & dosagem , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/epidemiologia , Doenças do Sistema Nervoso Periférico/genética , Prognóstico , Estudos Prospectivos , Taxa de SobrevidaRESUMO
l-3,4-dihydroxyphenylalanine (l-DOPA) is a candidate neurotransmitter. l-DOPA is released by nicotine through nicotinic receptors. Recently, G-protein coupled receptor GPR143, was identified as a receptor for l-DOPA. In this study, genetic association studies between GPR143 genetic polymorphisms and smoking behaviors revealed that the single-nucleotide polymorphism rs6640499, in the GPR143 gene, was associated with traits of smoking behaviors in Japanese individuals. In Gpr143 gene-deficient mice, nicotine-induced hypolocomotion and rewarding effect were attenuated compared to those in wild-type mice. Our findings suggest the involvement of GPR143 in the smoking behaviors.
Assuntos
Proteínas do Olho/genética , Deleção de Genes , Estudos de Associação Genética , Glicoproteínas de Membrana/genética , Nicotina/efeitos adversos , Polimorfismo de Nucleotídeo Único , Receptores Acoplados a Proteínas G/genética , Receptores de Neurotransmissores/genética , Reforço Psicológico , Transtornos Relacionados ao Uso de Substâncias/genética , Animais , Povo Asiático , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Índice de Gravidade de DoençaRESUMO
Growth and developmental processes are occasionally accompanied by multiple rounds of DNA replication, known as endoreduplication. Coordination between endoreduplication and cell size regulation often plays a crucial role in proper organogenesis and cell differentiation. Here, we report that the level of correlation between ploidy and cell volume is different in the outer and inner cell layers of leaves of Arabidopsis thaliana using a novel imaging technique. Although there is a well-known, strong correlation between ploidy and cell volume in pavement cells of the epidermis, this correlation was extremely weak in palisade mesophyll cells. Induction of epidermis cell identity based on the expression of the homeobox gene ATML1 in mesophyll cells enhanced the level of correlation between ploidy and cell volume to near that of wild-type epidermal cells. We therefore propose that the correlation between ploidy and cell volume is regulated by cell identity.
Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/crescimento & desenvolvimento , Tamanho Celular , Endorreduplicação/genética , Proteínas de Homeodomínio/metabolismo , Células do Mesofilo/citologia , Folhas de Planta/citologia , Proteínas de Arabidopsis/biossíntese , Proteínas de Arabidopsis/genética , Diferenciação Celular/genética , Regulação da Expressão Gênica de Plantas , Proteínas de Homeodomínio/biossíntese , Proteínas de Homeodomínio/genética , Células do Mesofilo/metabolismo , Epiderme Vegetal/citologia , Epiderme Vegetal/crescimento & desenvolvimento , Folhas de Planta/crescimento & desenvolvimento , Plantas Geneticamente Modificadas/metabolismo , PloidiasRESUMO
Background: Promoting continued physical activity during winter in snowy-cold regions would be of benefit as a health promotion strategy among elderly individuals. Aim: To evaluate the effect of a lower limb strength training programme for elderly individuals on the daily step counts during the snowy season. Subjects and methods: Fourteen community-dwelling elderly individuals were recruited from a snowy-cold region of northern Japan. Methods: Daily step counts were measured during the snowy season in 2018 (with no exercise intervention) and 2019 (after the exercise intervention). Physical function was measured before and after the intervention, including body mass index, 30-s chair test, grip strength, normal gait speed, short-test battery for locomotive syndrome, Kihon checklist and 25-question geriatric locomotive function scale. Results: The study group included 11 women and three men (78.6 ± 5.2 years old). The exercise intervention improved physical function, with a significant increase in step count among individuals with lower baseline strength. Improved lower limb strength positively correlated with an increase in step count. Conclusion: Lower limb muscle strengthening is an effective intervention to improve physical activity during the snowy season among community-dwelling elderly.
Assuntos
Exercício Físico , Vida Independente/estatística & dados numéricos , Extremidade Inferior/fisiologia , Treinamento Resistido/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Japão , Masculino , Estações do Ano , NeveRESUMO
Plants have various defense mechanisms against environmental stresses that induce DNA damage. Genetic and biochemical analyses have revealed the sensing and signaling of DNA damage, but little is known about subnuclear dynamics in response to DNA damage in living plant cells. Here, we observed that the chromatin remodeling factor RAD54, which is involved in DNA repair via the homologous recombination pathway, formed subnuclear foci (termed RAD54 foci) in Arabidopsis thaliana after induction of DNA double-strand breaks. The appearance of RAD54 foci was dependent on the ATAXIA-TELANGIECTASIA MUTATED-SUPPRESSOR OF GAMMA RESPONSE 1 pathway, and RAD54 foci were co-localized with γH2AX signals. Laser irradiation of a subnuclear area demonstrated that in living cells RAD54 was specifically accumulated at the damaged site. In addition, the formation of RAD54 foci showed specificity for cell type and region. We conclude that RAD54 foci correspond to DNA repair foci in A. thaliana.
Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Dano ao DNA/fisiologia , DNA Helicases/metabolismo , Reparo do DNA/fisiologia , Arabidopsis/genética , Proteínas de Arabidopsis/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Dano ao DNA/genética , DNA Helicases/genética , Reparo do DNA/genéticaRESUMO
BACKGROUND: The seven-valent pneumococcal conjugate vaccine (PCV7) was introduced to Japan in 2009, after which there was a rapid decline in invasive pneumococcal disease. There are few data, however, on the effectiveness of PCV7 against community-acquired pneumonia (CAP). We conducted an ambispective cohort study among children aged 0-6 years old who attended day-care centers. METHODS: A total of 624 children at 10 day-care centers in Sapporo, Japan participated in the study. The parents reported whether their child had received PCV7 one or more times, as well as the exact dates of vaccination from records in maternal and child health handbooks marked by pediatricians. Each CAP event was reported by parents according to doctor diagnosis. A Cox proportional hazards regression model was used to calculate the hazard ratio (HR) and 95%CI of CAP incidence reduced by PCV7 inoculation. RESULTS: During the observational period, 94 subjects contracted CAP. After adjusting for potentially confounding variables, inoculation with PCV7 was significantly associated with a reduced risk of CAP (HR, 0.22; 95%CI: 0.13-0.34). On stratified analysis by age, PCV7 was significantly associated with a reduced risk of CAP in both children aged <3 years (HR, 0.31; 95%CI: 0.14-0.71), and those ≥3 years (HR, 0.20; 95%CI: 0.09-0.43). CONCLUSION: PCV7 is highly effective in reducing the risk of CAP in children attending day-care centers.
Assuntos
Vacina Pneumocócica Conjugada Heptavalente , Pneumonia Pneumocócica/prevenção & controle , Criança , Creches , Pré-Escolar , Infecções Comunitárias Adquiridas/epidemiologia , Infecções Comunitárias Adquiridas/prevenção & controle , Feminino , Inquéritos Epidemiológicos , Humanos , Incidência , Lactente , Recém-Nascido , Japão/epidemiologia , Masculino , Pneumonia Pneumocócica/epidemiologia , Modelos de Riscos Proporcionais , Estudos Prospectivos , Estudos RetrospectivosRESUMO
Background Fentanyl is often used instead of morphine for the treatment of pain because it has fewer side effects. The metabolism of morphine by glucuronidation is known to be influenced by polymorphisms of the UGT2B7 gene. Some metabolic products of fentanyl are reportedly metabolized by glucuronate conjugation. The genes that are involved in the metabolic pathway of fentanyl may also influence fentanyl sensitivity. We analyzed associations between fentanyl sensitivity and polymorphisms of the UGT2B7 gene to clarify the hereditary determinants of individual differences in fentanyl sensitivity. Results This study examined whether single-nucleotide polymorphisms (SNPs) of the UGT2B7 gene affect cold pain sensitivity and the analgesic effects of fentanyl, evaluated by a standardized pain test and fentanyl requirements in healthy Japanese subjects who underwent uniform surgical procedures. The rs7439366 SNP of UGT2B7 is reportedly associated with the metabolism and analgesic effects of morphine. We found that this SNP is also associated with the analgesic effects of fentanyl in the cold pressor-induced pain test. It suggested that the C allele of the rs7439366 SNP may enhance analgesic efficacy. Two SNPs of UGT2B7, rs4587017 and rs1002849, were also found to be novel SNPs that may influence the analgesic effects of fentanyl in the cold pressor-induced pain test. Conclusions Fentanyl sensitivity for cold pressor-induced pain was associated with the rs7439366, rs4587017, and rs1002849 SNPs of the UGT2B7 gene. Our findings may provide valuable information for achieving satisfactory pain control and open to new avenues for personalized pain treatment.
Assuntos
Fentanila/uso terapêutico , Glucuronosiltransferase/genética , Cirurgia Ortognática , Polimorfismo de Nucleotídeo Único/genética , Adolescente , Adulto , Analgésicos Opioides/uso terapêutico , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Morfina/uso terapêutico , Medição da Dor/métodos , Limiar da Dor/efeitos dos fármacos , Dor Pós-Operatória/tratamento farmacológico , Adulto JovemRESUMO
Clearing techniques eliminate factors that interfere with microscopic observation, including light scattering and absorption by pigments and cytoplasmic components. The techniques allow fluorescence-based detailed analyses of materials and characterization of the three-dimensional structure of organs. We describe a simple and rapid clearing and imaging method, termed 'TOMEI' (Transparent plant Organ MEthod for Imaging), which enables microscopic observation of intact plant organs. This method involves a clearing reagent containing 2,2'-thiodiethanol. Conveniently, transparent plant organs were prepared within only 3-6 h. We detected fluorescent stains at a depth of approximately 200 µm using confocal laser scanning microscopy and analyzed fluorescent proteins in internal tissues of transparent organs cleared using TOMEI. We adapted TOMEI for various plant organs of Arabidopsis thaliana and Oryza sativa, including leaves, flower buds, flower stalks, root and nematode-infected root-knots. We visualized whole leaves of A. thaliana from the adaxial epidermis to the abaxial epidermis as well as protoxylem and metaxylem vessels of vascular bundles embedded in spongy mesophyll cells. Inner floral organs were observed in flower buds cleared using TOMEI without the need to prepare sections or remove sepals. Multicolor imaging of fluorescent proteins and dyes, and analyses of the three-dimensional structure of plant organs based on optical sections are possible using TOMEI. We analyzed root-knots cleared using TOMEI and revealed that nematodes induce giant cell expansion in a DNA content-dependent manner. The TOMEI method is applicable to analysis of fluorescent proteins and dyes quantitatively with cell morphological characteristics in whole plant organs.