Tsc2 mutation rather than Tsc1 mutation dominantly causes a social deficit in a mouse model of tuberous sclerosis complex.

BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that is associated with neurological symptoms, including autism spectrum disorder. Tuberous sclerosis complex is caused by pathogenic germline mutations of either the TSC1 or TSC2 gene, but somatic mutations were identified in both genes, and the combined effects of TSC1 and TSC2 mutations have been unknown. METHODS: The present study investigated social behaviors by the social interaction test and three-chambered sociability tests, effects of rapamycin treatment, and gene expression profiles with a gene expression microarray in Tsc1 and Tsc2 double heterozygous mutant (TscD+/-) mice. RESULTS: TscD+/- mice exhibited impairments in social behaviors, and the severity of impairments was similar to Tsc2+/- mice rather than Tsc1+/- mice. Impairments in social behaviors were rescued by rapamycin treatment in all mutant mice. Gene expression profiles in the brain were greatly altered in TscD+/- mice more than in Tsc1+/- and Tsc2+/- mice. The gene expression changes compared with wild type (WT) mice were similar between TscD+/- and Tsc2+/- mice, and the overlapping genes whose expression was altered in mutant mice compared with WT mice were enriched in the neoplasm- and inflammation-related canonical pathways. The "signal transducer and activator of transcription 3, interferon regulatory factor 1, interferon regulatory factor 4, interleukin-2R α chain, and interferon-γ" signaling pathway, which is initiated from signal transducer and activator of transcription 4 and PDZ and LIM domain protein 2, was associated with impairments in social behaviors in all mutant mice. LIMITATIONS: It is unclear whether the signaling pathway also plays a critical role in autism spectrum disorders not caused by Tsc1 and Tsc2 mutations. CONCLUSIONS: These findings suggest that TSC1 and TSC2 double mutations cause autistic behaviors similarly to TSC2 mutations, although significant changes in gene expression were attributable to the double mutations. These findings contribute to the knowledge of genotype-phenotype correlations in TSC and suggest that mutations in both the TSC1 and TSC2 genes act in concert to cause neurological symptoms, including autism spectrum disorder.

Genome-Wide Association Study Identifies Genetic Polymorphisms Associated with Estimated Minimum Effective Concentration of Fentanyl in Patients Undergoing Laparoscopic-Assisted Colectomy.

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.

Rs11726196 Single-Nucleotide Polymorphism of the Transient Receptor Potential Canonical 3 (TRPC3) Gene Is Associated with Chronic Pain.

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.

Magnetization Precession at Sub-Terahertz Frequencies in Polycrystalline Cu2 Sb-Type (Mn-Cr)AlGe Ultrathin Films.

A ferromagnetic metal nanolayer with a large perpendicular magnetic anisotropy, small saturation magnetization, and small magnetic damping constant is a crucial requirement for high-speed spintronic devices. Fabrication of these devices on Si/SiO2 amorphous substrates with polycrystalline structure is also strongly desired for the mass production industry. This study involves the investigation of sub-terahertz (THz) magnetization precessional motion in a newly developed material system consisting of Cu2 Sb-type MnAlGe and (Mn-Cr)AlGe films by means of an all-optical pump-probe method. These materials exhibit large perpendicular magnetic anisotropy in regions of a few nanometers in size. The pseudo-2D crystal structures are clearly observed in the high-resolution transmission electron microscopy (TEM) images for the film samples grown on thermally oxidized silicon substrates. The TEM images also show a partial substitution of Cr atoms for the Mn sites in MnAlGe. A magnetization precession frequency of 0.164 THz with a relatively small effective magnetic damping constant of 0.012 is obtained for (Mn-Cr)AlGe. Theoretical calculation infers that the modification of the total density of states by Cr substitution decreases the intrinsic magnetic damping constant of (Mn-Cr)AlGe.

Heparan sulfate 3-O-sulfotransferase 4 is genetically associated with herpes zoster and enhances varicella-zoster virus-mediated fusogenic activity.

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.

Genome-wide association study identifies candidate loci associated with chronic pain and postherpetic neuralgia.

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.

Genome-wide association study identifies polymorphisms associated with the analgesic effect of fentanyl in the preoperative cold pressor-induced pain test.

Opioid analgesics are widely used for the treatment of moderate to severe pain. The analgesic effects of opioids are well known to vary among individuals. The present study focused on the genetic factors that are associated with interindividual differences in pain and opioid sensitivity. We conducted a multistage genome-wide association study in subjects who were scheduled to undergo mandibular sagittal split ramus osteotomy and were not medicated until they received fentanyl for the induction of anesthesia. We preoperatively conducted the cold pressor-induced pain test before and after fentanyl administration. The rs13093031 and rs12633508 single-nucleotide polymorphisms (SNPs) near the LOC728432 gene region and rs6961071 SNP in the tcag7.1213 gene region were significantly associated with the analgesic effect of fentanyl, based on differences in pain perception latency before and after fentanyl administration. The associations of these three SNPs that were identified in our exploratory study have not been previously reported. The two polymorphic loci (rs13093031 and rs12633508) were shown to be in strong linkage disequilibrium. Subjects with the G/G genotype of the rs13093031 and rs6961071 SNPs presented lower fentanyl-induced analgesia. Our findings provide a basis for investigating genetics-based analgesic sensitivity and personalized pain control.

Association between UGT2B7 gene polymorphisms and fentanyl sensitivity in patients undergoing painful orthognathic surgery.

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.

[Case Report : Monitored Anesthesia Care (MAC) with Dexmedetomidine.]

Dexmedetomidine (DEX) is a sedative used for monitored anesthesia care (MAC). DEX has been used frequently for MAC because of its less respiratory depressant effect We used DEX in four patients with severe complications who needed surgery under MAC. We started MAC with continuous infusion of 0.5-0.9 µtg - kg(-1) . hr(-1) of DEX, without initial loading dose, combined with regional anesthesia, and gradually either increased or decreased continuous infusion according to Ramsay sedation scale (RSS). The simulated plasma concentrations of DEX were calculated by AnestAs- sistTM PK . PD(-1). All patients were well sedated and operations were completed safely, although simulated plasma concentrations of DEX were low. Remarkable cardiovascular responses and respiratory depression were not observed. Our study indicated that the usage of DEX without initial loading dose combined with regional anesthesia could be an option for patients with severe complications undergoing MAC.

Association between the rs1465040 single-nucleotide polymorphism close to the transient receptor potential subfamily C member 3 (TRPC3) gene and postoperative analgesic requirements.

An association between postoperative analgesic requirements in subjects who underwent orthognathic surgery and the rs1465040 single-nucleotide polymorphism close to the transient receptor potential subfamily C member 3 (TRPC3) gene was suggested by our previous genome-wide association study. To verify this association, we analyzed the association between the rs1465040 SNP and analgesic requirements, including opioid requirements, after open abdominal surgery. The association between the rs1465040 SNP and postoperative analgesic requirements was confirmed in the open abdominal surgery group (P = 0.036), suggesting that the TRPC3 SNP may contribute to predicting postoperative analgesic requirements.

Large positive magnetoresistive effect in silicon induced by the space-charge effect.

Recent discoveries of large magnetoresistance in non-magnetic semiconductors have gained much attention because the size of the effect is comparable to, or even larger than, that of magnetoresistance in magnetic systems. Conventional magnetoresistance in doped semiconductors is straightforwardly explained as the effect of the Lorentz force on the carrier motion, but the reported unusually large effects imply that the underlying mechanisms have not yet been fully explored. Here we report that a simple device, based on a lightly doped silicon substrate between two metallic contacts, shows a large positive magnetoresistance of more than 1,000 per cent at room temperature (300 K) and 10,000 per cent at 25 K, for magnetic fields between 0 and 3 T. A high electric field is applied to the device, so that conduction is space-charge limited. For substrates with a charge carrier density below approximately 10(13) cm(-3), the magnetoresistance exhibits a linear dependence on the magnetic field between 3 and 9 T. We propose that the observed large magnetoresistance can be explained by quasi-neutrality breaking of the space-charge effect, where insufficient charge is present to compensate the electrons injected into the device. This introduces an electric field inhomogeneity, analogous to the situation in other semiconductors in which a large, non-saturating magnetoresistance was observed. In this regime, the motions of electrons become correlated, and thus become dependent on magnetic field. Although large positive magnetoresistance at room temperature has been achieved in metal-semiconductor hybrid devices, we have now realized it in a simpler structure and in a way different from other known magnetoresistive effects. It could be used to develop new magnetic devices from silicon, which may further advance silicon technology.

Haplotypes of P2RX7 gene polymorphisms are associated with both cold pain sensitivity and analgesic effect of fentanyl.

BACKGROUND: The P2X7 receptor is a member of the P2X family of adenosine 5'-triphosphate-gated cation channels. Several recent studies have demonstrated that this receptor is involved in mechanisms related to pain and inflammation. However, unknown is whether polymorphisms of the P2RX7 gene that encodes the human P2X7 receptor influence pain sensitivity and analgesic effects of opioids. The P2RX7 gene is known to be highly polymorphic. Thus, the present study examined associations between fentanyl sensitivity and polymorphisms in the P2RX7 gene in 355 Japanese patients who underwent painful orofacial cosmetic surgery. RESULTS: We first conducted linkage disequilibrium (LD) analyses for 55 reported single-nucleotide polymorphisms (SNPs) in the region within and around the P2RX7 gene using genomic samples from 100 patients. In our samples, 42 SNPs were polymorphic, and a total of five LD blocks with six Tag SNPs (rs2708092, rs1180012, rs1718125, rs208293, rs1718136, and rs7132846) were observed. Thus, we further analyzed associations between genotypes/haplotypes of these Tag SNPs and clinical data using a total of 355 samples. In the genotype-based association study, only the rs1718125 G>A SNP tended to be associated with higher pain scores on a visual analog scale 24 h after surgery (VAS24). The haplotype-based association study showed that subjects with homozygous haplotype No.3 (GTAAAC; estimated frequency: 15.0%) exhibited significantly higher cold pain sensitivity and lower analgesic effects of fentanyl for acute cold pain in the cold pressor test. Conversely, subjects who carried haplotype No.1 (ACGGAC; estimated frequency: 24.5%) tended to exhibit lower cold pain sensitivity and higher analgesic effects of fentanyl. Furthermore, subjects with homozygous haplotype No.2 (GCGGAC; estimated frequency: 22.9%) exhibited significantly lower VAS24 scores. CONCLUSIONS: Cold pain sensitivity and analgesic effects of fentanyl were related to the SNP and haplotypes of the P2RX7 gene. The patients with the rs1718125 G>A SNP tended to show higher VAS24 scores. Moreover, the combination of polymorphisms from the 5'-flanking region to exon 5 recessively affected cold pain sensitivity and analgesic effects of opioids for acute cold pain. The present findings shed light on the involvement of P2RX7 gene polymorphisms in naive cold pain sensitivity and analgesic effects of fentanyl.

Association between KCNJ6 (GIRK2) gene polymorphism rs2835859 and post-operative analgesia, pain sensitivity, and nicotine dependence.

G-protein-activated inwardly rectifying potassium (GIRK) channels are expressed in many tissues and activated by several Gi/o protein-coupled receptors, such as opioid and dopamine receptors, and thus are known to be involved in the modulation of opioid-induced analgesia, pain, and reward. We focused on a GIRK-channel subunit that plays a pivotal role in the brain, GIRK2, and investigated the contribution of genetic variations of the GIRK2 (KCNJ6) gene to individual differences in the sensitivity to opioid analgesia. In our initial linkage disequilibrium analysis, a total of 27 single-nucleotide polymorphisms (SNPs) were selected within and around the regions of the KCNJ6 gene. Among them, the rs2835859 SNP, for which associations with analgesia and pain have not been previously reported, was selected in the exploratory study as a potent candidate SNP associated with opioid analgesic sensitivity. The results were corroborated in further confirmatory study. Interestingly, this SNP was also found to be associated with sensitivity to both cold and mechanical pain, susceptibility to nicotine dependence, and successful smoking cessation. The results indicate that this SNP could serve as a marker that predicts sensitivity to analgesic and pain and susceptibility to nicotine dependence.

Genome-wide association study of sensory disturbances in the inferior alveolar nerve after bilateral sagittal split ramus osteotomy.

BACKGROUND: Bilateral sagittal split ramus osteotomy (BSSRO) is a common orthognatic surgical procedure. Sensory disturbances in the inferior alveolar nerve, including hypoesthesia and dysesthesia, are frequently observed after BSSRO, even without distinct nerve injury. The mechanisms that underlie individual differences in the vulnerability to sensory disturbances have not yet been elucidated. METHODS: The present study investigated the relationships between genetic polymorphisms and the vulnerability to sensory disturbances after BSSRO in a genome-wide association study (GWAS). A total of 304 and 303 patients who underwent BSSRO were included in the analyses of hypoesthesia and dysesthesia, respectively. Hypoesthesia was evaluated using the tactile test 1 week after surgery. Dysesthesia was evaluated by interview 4 weeks after surgery. Whole-genome genotyping was conducted using Illumina BeadChips including approximately 300,000 polymorphism markers. RESULTS: Hypoesthesia and dysesthesia occurred in 51 (16.8%) and 149 (49.2%) subjects, respectively. Significant associations were not observed between the clinical data (i.e., age, sex, body weight, body height, loss of blood volume, migration length of bone fragments, nerve exposure, duration of anesthesia, and duration of surgery) and the frequencies of hypoesthesia and dysesthesia. Significant associations were found between hypoesthesia and the rs502281 polymorphism (recessive model: combined χ² = 24.72, nominal P = 6.633 × 10⁻7), between hypoesthesia and the rs2063640 polymorphism (recessive model: combined χ² = 23.07, nominal P = 1.563 × 10⁻6), and between dysesthesia and the nonsynonymous rs2677879 polymorphism (trend model: combined χ² = 16.56, nominal P = 4.722 × 10⁻5; dominant model: combined χ² = 16.31, nominal P = 5.369 × 10⁻5). The rs502281 and rs2063640 polymorphisms were located in the flanking region of the ARID1B and ZPLD1 genes on chromosomes 6 and 3, whose official names are "AT rich interactive domain 1B (SWI1-like)" and "zona pellucida-like domain containing 1", respectively. The rs2677879 polymorphism is located in the METTL4 gene on chromosome 18, whose official name is "methyltransferase like 4". CONCLUSIONS: The GWAS of sensory disturbances after BSSRO revealed associations between genetic polymorphisms located in the flanking region of the ARID1B and ZPLD1 genes and hypoesthesia and between a nonsynonymous genetic polymorphism in the METTL4 gene and dysesthesia.

Association between genetic polymorphisms of the ß1-adrenergic receptor and sensitivity to pain and fentanyl in patients undergoing painful cosmetic surgery.

Individual differences in the sensitivity to fentanyl, a widely used opioid analgesic, can hamper effective pain treatment. The adrenergic system is reportedly involved in the mechanisms of pain and analgesia. Here, we focused on one of the adrenergic receptor genes, ADRB1, and analyzed the influence of single-nucleotide polymorphisms (SNPs) in the ADRB1 gene on individual differences in pain and analgesic sensitivity. We examined associations between pain and fentanyl sensitivity and the two SNPs, A145G and G1165C, in the human ADRB1 gene in 216 Japanese patients who underwent painful orofacial cosmetic surgery, including bone dissection. The patients who carried the A-allele of the A145G SNP were more sensitive to cold pressor- induced pain than those who did not carry this allele, especially in male patients. The analgesic effect was significantly less in females who carried the G-allele of the G1165C SNP than the females who did not carry the G-allele. The haplotype analysis revealed a significant decrease in 24-h postoperative fentanyl use in female 145A/1165C haplotype carriers. These results suggest that SNPs in the ADRB1 gene are associated with individual differences in pain and analgesic sensitivity, and analyzing these SNPs may promote personalized pain treatment in the future.

Fentanyl-induced muscle rigidity in a dog during weaning from mechanical ventilation after emergency abdominal surgery: A case report.

A 22.5-kg, 8.4-year-old female mixed breed dog was presented for an emergency ovariohysterectomy for pyometra. No neurological abnormalities were observed on preoperative physical examination. Surgery was completed uneventfully under fentanyl- and sevoflurane-based anaesthesia. Cardiorespiratory indices remained stable under mechanical ventilation throughout the procedure. Approximately 23 min after the discontinuation of fentanyl infusion, the investigator noticed jaw closure and stiffness and thoraco-abdominal muscle rigidity. To rule out fentanyl-induced muscle rigidity, naloxone was administered. Following administration of naloxone, there was a return of spontaneous respiratory effort, indicated by capnogram and visible chest wall excursion. Based on the clinical signs and response to naloxone administration, the dog was diagnosed with suspected fentanyl-induced muscle rigidity. Six minutes after the return of spontaneous respiration, the dog was extubated uneventfully without additional naloxone administration. During 4 days of postoperative hospitalization, no recurrent muscle rigidity was observed, and the patient was discharged safely. The total dose of fentanyl administered was 0.61 mg (27 µg kg-1 ).

Genome-Wide Association Study Identifies Novel Candidate Variants Associated with Postoperative Nausea and Vomiting.

Considerable individual differences are widely observed in the incidence of postoperative nausea and vomiting (PONV). We conducted a genome-wide association study (GWAS) to identify potential candidate single-nucleotide polymorphisms (SNPs) that contribute to PONV by utilizing whole-genome genotyping arrays with more than 950,000 markers. The subjects were 806 patients who provided written informed consent and underwent elective surgery under general anesthesia with propofol or desflurane. The GWAS showed that two SNPs, rs2776262 and rs140703637, in the LOC100506403 and CNTN5 gene regions, respectively, were significantly associated with the frequency of nausea. In another GWAS conducted only on patients who received propofol, rs7212072 and rs12444143 SNPs in the SHISA6 and RBFOX1 gene regions, respectively, were significantly associated with the frequency of nausea as well as the rs2776262 SNP, and the rs45574836 and rs1752136 SNPs in the ATP8B3 and LOC105370198 gene regions, respectively, were significantly associated with vomiting. Among these SNPs, clinical and SNP data were available for the rs45574836 SNP in independent subjects who underwent laparoscopic gynecological surgery, and the association was replicated in these subjects. These results indicate that these SNPs could serve as markers that predict the vulnerability to PONV. Our findings may provide valuable information for achieving satisfactory prophylactic treatment for PONV.

[The association between beta-adrenergic receptor gene polymorphisms and personality traits].

The relationship between the polymorphisms (SNPs) of the beta-adrenergic receptor (beta-AR) gene and personality assessed by TCI (Temperament and Character Inventory), was studied among 192 healthy Japanese subjects (121 male subjects and 71 female subjects). In this study, the statistical analyses were performed overall and separately for each sex. As a result, it was shown that there were significant relationships between SD (self-directedness) and 49Ser/Gly (rs1801252) in ADRB1, P (persistence) and 389Arg/Gly (rs1801253) in ADRB1, and ST (self-transcendence) and 27Gln/Glu (rs1042714) in ADRB2 overall. Among the male subjects, there were further significant relationships between ST and 49Ser/Gly in ADRB1, NS (novelty-seeking), HA (harm avoidance) and P and 389Arg/Gly in ADRB1, and P and 64Arg/Trp(rsrs4994) in ADRB3. Among the female subjects, there were also significant relationships between SD and 49Ser/Gly in ADRB1, and C (cooperativeness) and 389Arg/Gly in ADRB1. Thus it was shown that there were correlations between beta-AR gene polymorphisms and several subscales of TCI.

Genome-Wide Association Study Identifies Candidate Loci Associated with Opioid Analgesic Requirements in the Treatment of Cancer Pain.

Considerable individual differences have been widely observed in the sensitivity to opioids. We conducted a genome-wide association study (GWAS) in patients with cancer pain to identify potential candidate single-nucleotide polymorphisms (SNPs) that contribute to individual differences in opioid analgesic requirements in pain treatment by utilizing whole-genome genotyping arrays with more than 650,000 markers. The subjects in the GWAS were 428 patients who provided written informed consent and underwent treatment for pain with opioid analgesics in a palliative care unit at Higashi-Sapporo Hospital. The GWAS showed two intronic SNPs, rs1283671 and rs1283720, in the ANGPT1 gene that encodes a secreted glycoprotein that belongs to the angiopoietin family. These two SNPs were strongly associated with average daily opioid requirements for the treatment of pain in both the additive and recessive models (p < 5.0000 × 10−8). Several other SNPs were also significantly associated with the phenotype. In the gene-based analysis, the association was significant for the SLC2A14 gene in the additive model. These results indicate that these SNPs could serve as markers that predict the efficacy of opioid analgesics in cancer pain treatment. Our findings may provide valuable information for achieving satisfactory pain control and open new avenues for personalized pain treatment.

Pattern recognition with neuromorphic computing using magnetic field-induced dynamics of skyrmions.

Nonlinear phenomena in physical systems can be used for brain-inspired computing with low energy consumption. Response from the dynamics of a topological spin structure called skyrmion is one of the candidates for such a neuromorphic computing. However, its ability has not been well explored experimentally. Here, we experimentally demonstrate neuromorphic computing using nonlinear response originating from magnetic field-induced dynamics of skyrmions. We designed a simple-structured skyrmion-based neuromorphic device and succeeded in handwritten digit recognition with the accuracy as large as 94.7% and waveform recognition. Notably, there exists a positive correlation between the recognition accuracy and the number of skyrmions in the devices. The large degrees of freedom of skyrmion systems, such as the position and the size, originate from the more complex nonlinear mapping, the larger output dimension, and, thus, high accuracy. Our results provide a guideline for developing energy-saving and high-performance skyrmion neuromorphic computing devices.