Expansion of the human mu-opioid receptor gene architecture: novel functional variants.

The mu-opioid receptor (OPRM1) is the principal receptor target for both endogenous and exogenous opioid analgesics. There are substantial individual differences in human responses to painful stimuli and to opiate drugs that are attributed to genetic variations in OPRM1. In searching for new functional variants, we employed comparative genome analysis and obtained evidence for the existence of an expanded human OPRM1 gene locus with new promoters, alternative exons and regulatory elements. Examination of polymorphisms within the human OPRM1 gene locus identified strong association between single nucleotide polymorphism (SNP) rs563649 and individual variations in pain perception. SNP rs563649 is located within a structurally conserved internal ribosome entry site (IRES) in the 5'-UTR of a novel exon 13-containing OPRM1 isoforms (MOR-1K) and affects both mRNA levels and translation efficiency of these variants. Furthermore, rs563649 exhibits very strong linkage disequilibrium throughout the entire OPRM1 gene locus and thus affects the functional contribution of the corresponding haplotype that includes other functional OPRM1 SNPs. Our results provide evidence for an essential role for MOR-1K isoforms in nociceptive signaling and suggest that genetic variations in alternative OPRM1 isoforms may contribute to individual differences in opiate responses.

A wearable ground reaction force sensor system and its application to the measurement of extrinsic gait variability.

Wearable sensors for gait analysis are attracting wide interest. In this paper, a wearable ground reaction force (GRF) sensor system and its application to measure extrinsic gait variability are presented. To validate the GRF and centre of pressure (CoP) measurements of the sensor system and examine the effectiveness of the proposed method for gait analysis, we conducted an experimental study on seven volunteer subjects. Based on the assessment of the influence of the sensor system on natural gait, we found that no significant differences were found for almost all measured gait parameters (p-values < 0.05). As for measurement accuracy, the root mean square (RMS) differences for the two transverse components and the vertical component of the GRF were 7.2% ± 0.8% and 9.0% ± 1% of the maximum of each transverse component and 1.5% ± 0.9% of the maximum vertical component of GRF, respectively. The RMS distance between both CoP measurements was 1.4% ± 0.2% of the length of the shoe. The area of CoP distribution on the foot-plate and the average coefficient of variation of the triaxial GRF, are the introduced parameters for analysing extrinsic gait variability. Based on a statistical analysis of the results of the tests with subjects wearing the sensor system, we found that the proposed parameters changed according to walking speed and turning (p-values < 0.05).

Reaction force/torque sensing in a master-slave robot system without mechanical sensors.

In human-robot cooperative control systems, force feedback is often necessary in order to achieve high precision and high stability. Usually, traditional robot assistant systems implement force feedback using force/torque sensors. However, it is difficult to directly mount a mechanical force sensor on some working terminals, such as in applications of minimally invasive robotic surgery, micromanipulation, or in working environments exposed to radiation or high temperature. We propose a novel force sensing mechanism for implementing force feedback in a master-slave robot system with no mechanical sensors. The system consists of two identical electro-motors with the master motor powering the slave motor to interact with the environment. A bimanual coordinated training platform using the new force sensing mechanism was developed and the system was verified in experiments. Results confirm that the proposed mechanism is capable of achieving bilateral force sensing and mirror-image movements of two terminals in two reverse control directions.

Computational Drug-repositioning Approach Identifying Sirolimus as a Potential Therapeutic Option for Inflammatory Dilated Cardiomyopathy.

OBJECTIVE: The aim of this study was to determine promising treatment options for human inflammatory dilated cardiomyopathy using a computational drug-repositioning approach (repurposing established drug compounds for new therapeutic indications). BACKGROUND: If the myocardial tissue is detected to be infiltrated with inflammatory cells, primarily of lymphocytes, and if the virus is confirmed using genetic examination (PCR) or immunostaining, the infection is suspected. However, there is no specific treatment (i. e., an antiviral drug) even if the virus is identified; therefore, we used Connectivity Map to identify compounds showing inverse drug-disease signatures, indicating activity against inflammatory dilated cardiomyopathy. RESULTS: Potential drug-repositioning candidates for the treatment of inflammatory dilated cardiomyopathy were explored through a systematic comparison of the gene expression profiles induced by drugs using Gene Expression Omnibus and Connectivity Map databases. CONCLUSION: Using a computational drug-repositioning approach based on the integration of publicly available gene expression signatures of drugs and diseases, sirolimus was suggested as a novel therapeutic option for inflammatory dilated cardiomyopathy.

Trajectories of Postload Plasma Glucose in the Development of Type 2 Diabetes in Japanese Adults.

We aimed to clarify how the trajectories of 1-hour postload plasma glucose (PG) and 2-hour PG were different in the development of type 2 diabetes. Using data of repeated health checkups in Japanese workers from April 2006 to March 2016, longitudinal changes of fasting, 1-hour, and 2-hour PG on the oral glucose tolerance test were analyzed with a linear mixed effects model. Of the 1464 nondiabetic subjects at baseline, 112 subjects progressed to type 2 diabetes during the observation period (progressors). In progressors, 1-hour PG and 2-hour PG showed gradual increases with slopes of 1.33 ± 0.2 and 0.58 ± 0.2 mg/dL/year, respectively, followed by a steep increase by which they attained diabetes. Until immediately before the diabetes transition, age- and sex-adjusted mean level of 2-hour PG was 149 ± 2.7 mg/dL, 34 ± 2.7 (30%) higher compared to nonprogressors, while that of 1-hour PG was 206 ± 4.1 mg/dL, 60 ± 4.3 mg/dL (41%) higher compared to nonprogressors. In conclusion, diabetes transition was preceded by a mild elevation of 2-hour PG for several years or more. The elevation in 1-hour PG was larger than that of 2-hour PG until immediately before the transition to diabetes.

Simultaneous estimation of haplotype frequencies and quantitative trait parameters: applications to the test of association between phenotype and diplotype configuration.

The analysis of the haplotype-phenotype relationship has become more and more important. We have developed an algorithm, using individual genotypes at linked loci as well as their quantitative phenotypes, to estimate the parameters of the distribution of the phenotypes for subjects with and without a particular haplotype by an expectation-maximization (EM) algorithm. We assumed that the phenotype for a diplotype configuration follows a normal distribution. The algorithm simultaneously calculates the maximum likelihood (L0max) under the null hypothesis (i.e., nonassociation between the haplotype and phenotype), and the maximum likelihood (Lmax) under the alternative hypothesis (i.e., association between the haplotype and phenotype). Then we tested the association between the haplotype and the phenotype using a test statistic, -2 log(L0max/Lmax). The above algorithm along with some extensions for different modes of inheritance was implemented as a computer program, QTLHAPLO. Simulation studies using single-nucleotide polymorphism (SNP) genotypes have clarified that the estimation was very accurate when the linkage disequilibrium between linked loci was rather high. Empirical power using the simulated data was high enough. We applied QTLHAPLO for the analysis of the real data of the genotypes at the calpain 10 gene obtained from diabetic and control subjects in various laboratories.

Relationship between oral Candida species and risk factors with reference to drugs with xerostomic side effects among institutionalised elderly in Aichi Pref., Japan.

OBJECTIVE: To clarify the relationship between Candida carriage and drugs which have reported xerostomic side effects in the elderly. DESIGN: Cross-sectional study. Setting Two long-term care facilities in Aichi Pref., Japan. PARTICIPANTS: Eight men and 63 women with a mean age of 86 years (range 62 to 95 years) with at least some of their natural teeth. METHOD: Oral examination by dentists, microbiological test by microbiologists, questionnaire interviews, and data obtained from medical files. The Candida species (CFU) was adopted as an objective variable with risk indicators being age, number of teeth, saliva flow rate, denture wearing, xerostomic drugs, activities of daily living (ADL), frequency of brushing and type of meals. RESULTS: Bivariate analysis confirmed that participants with a higher number of Candida species (CFU) fell into the following categories: denture wearing (p < 0.05), older age (p < 0.05), xerostomic drugs (p < 0.10), more teeth, poor ADL, soft/liquid meals, and brushing once a day. This was in contrast to the categories of no denture wearing, younger age, no xerostomic drugs, fewer teeth, good ADL, normal meals, and brushing two or more times a day, in that order of significant probability on an ascending scale. A multiple logistics regression model confirmed that the variables of older age (80 years and over) and more teeth (six or more) had statistically significant (p < 0.05) effects on the number of Candida species present (CFU). Xerostomic drugs and the other variables had no significant effect. CONCLUSION: Older age and more teeth had a significant effect on the number of oral Candida species in the elderly. The results of this study did not support a role of those drugs as a risk indicator for oral Candida carriage. Larger trials are needed to assess the effect of drugs on the presence of oral Candida.

The confounding effect of cryptic relatedness for environmental risks of systolic blood pressure on cohort studies.

The impact of cryptic relatedness (CR) on genomic association studies is well studied and known to inflate false-positive rates as reported by several groups. In contrast, conventional epidemiological studies for environmental risks, the confounding effect of CR is still uninvestigated. In this study, we investigated the confounding effect of unadjusted CR among a rural cohort in the relationship between environmental risk factors (body mass index, smoking status, alcohol consumption) and systolic blood pressure. We applied the methods of population-based whole-genome association studies for the analysis of the genome-wide single nucleotide polymorphism data in 1622 subjects, and detected 20.2% CR in this cohort population. In the case of the sample size, approximately 1000, the ratio of CR to the population was 20.2%, the population prevalence 25%, the prevalence in the CR 26%, heritability for liability 14.3% and prevalence in the subpopulation without CR 26%, the difference of estimated regression coefficient between samples with and without CR was not significant (P-value = 0.55). On the other hand, in another case with approximately >20% heritability for liability, we showed that confounding due to CR biased the estimation of exposure effects.

Physical sensor difference-based method and virtual sensor difference-based method for visual and quantitative estimation of lower limb 3D gait posture using accelerometers and magnetometers.

An approach using a physical sensor difference-based algorithm and a virtual sensor difference-based algorithm to visually and quantitatively confirm lower limb posture was proposed. Three accelerometers and two MAG(3)s (inertial sensor module) were used to measure the accelerations and magnetic field data for the calculation of flexion/extension (FE) and abduction/adduction (AA) angles of hip joint and FE, AA and internal/external rotation (IE) angles of knee joint; then, the trajectories of knee and ankle joints were obtained with the joint angles and segment lengths. There was no integration of acceleration or angular velocity for the joint rotations and positions, which is an improvement on the previous method in recent literature. Compared with the camera motion capture system, the correlation coefficients in five trials were above 0.91 and 0.92 for the hip FE and AA, respectively, and higher than 0.94, 0.93 and 0.93 for the knee joint FE, AA and IE, respectively.

Ambulatory estimation of knee-joint kinematics in anatomical coordinate system using accelerometers and magnetometers.

Knee-joint kinematics analysis using an optimal sensor set and a reliable algorithm would be useful in the gait analysis. An original approach for ambulatory estimation of knee-joint angles in anatomical coordinate system is presented, which is composed of a physical-sensor-difference-based algorithm and virtual-sensor-difference-based algorithm. To test the approach, a wearable monitoring system composed of accelerometers and magnetometers was developed and evaluated on lower limb. The flexion/extension (f/e), abduction/adduction (a/a), and inversion/extension (i/e) rotation angles of the knee joint in the anatomical joint coordinate system were estimated. In this method, since there is no integration of angular acceleration or angular velocity, the result is not distorted by offset and drift. The three knee-joint angles within the anatomical coordinate system are independent of the orders, which must be considered when Euler angles are used. Besides, since there are no physical sensors implanted in the knee joint based on the virtual-sensor-difference-based algorithm, it is feasible to analyze knee-joint kinematics with less numbers and types of sensors than those mentioned in some others methods. Compared with results from the reference system, the developed wearable sensor system is available to do gait analysis with fewer sensors and high degree of accuracy.

Evaluation of a bimanual-coordinated upper-limbs training system based on the near infrared spectroscopic signals on brain.

Various rehabilitation systems have been developed to deliver therapy for hemiplegic patients. Fugl- Meyer scale and Motor Power Score were common used methods to evaluate training effect and validate the developed systems. However, these assessments were involved with some inevitable subjective factors of therapists. In order to objectively evaluate the effect of a bimanual training that performed with a novel self-controlled system, this paper carried out assessment based on cerebral activation and motion-tracking precision. Four healthy subjects coordinated the forces of two arms and performed motion tracking training in active-assisted and active-resisted modes. After training, movement performance was enhanced and the brain became more active with an increased cerebral activation. Experimental results verified the positive training effect of the new system and the correlation between the cerebral cortical activation and motion capability.

Regiospecific profiles of fatty acids in triacylglycerols and phospholipids from Adzuki beans (Vigna angularis).

Regiospecific distributions of fatty acids (FA) of triacylglycerols (TAG) and phospholipids (PL) isolated from five cultivars of adzuki beans (Vigna angularis) were investigated. The lipids comprised mainly PL (72.2-73.4 wt-%) and TAG (20.6-21.9 wt-%), whilst other components were detected in minor proportions (0.1-3.4 wt-%). The principal profiles of the FA distribution in the TAG and PL were evident in the beans among the five cultivars: unsaturated FA were predominantly distributed in the sn-2 position, whilst saturated FA primarily occupied the sn-1 or the sn-3 position in the these lipids. The results would be useful information to both producers and consumers for manufacturing traditional adzuki confectionaries such as wagashi in Japan.

Haplotype associations with quantitative traits in the presence of complex multilocus and heterogeneous effects.

In genetic mapping of complex traits, scored haplotypes are likely to represent only a subset of all causal polymorphisms. At the extreme of this scenario, observed polymorphisms are not themselves functional, and only linked to causal ones via linkage disequilibrium (LD). We will demonstrate that due to such incomplete knowledge regarding the underlying genetic mechanism, the variance of a trait may become different between the scored haplotypes. Thus, unequal variances between haplotypes may be indicative of additional functional polymorphisms affecting the trait. Methods accounting for such haplotype-specific variance may also provide an increased power to detect complex associations. We suggest ways to estimate and test these haplotypic variance contrasts, and incorporate them into the haplotypic tests for association. We further extend this approach to data with unknown gametic phase via likelihood-based simultaneous estimation of haplotypic effects and their frequencies. We find our approach to provide additional power, especially under the following types of models: (a) where scored and unobserved variants are epistatically interacting with each other; and (b) under heterogeneity models, where multiple unobserved mutations are linked to non-functional observed polymorphisms via LD. An illustrative example of usefulness of the method is discussed, utilizing analysis of multilocus effects within the catechol-O-methyltransferase gene.

Novel approach to ambulatory assessment of human segmental orientation on a wearable sensor system.

A new method using a double-sensor difference based algorithm for analyzing human segment rotational angles in two directions for segmental orientation analysis in the three-dimensional (3D) space was presented. A wearable sensor system based only on triaxial accelerometers was developed to obtain the pitch and yaw angles of thigh segment with an accelerometer approximating translational acceleration of the hip joint and two accelerometers measuring the actual accelerations on the thigh. To evaluate the method, the system was first tested on a 2 degrees of freedom mechanical arm assembled out of rigid segments and encoders. Then, to estimate the human segmental orientation, the wearable sensor system was tested on the thighs of eight volunteer subjects, who walked in a straight forward line in the work space of an optical motion analysis system at three self-selected speeds: slow, normal and fast. In the experiment, the subject was assumed to walk in a straight forward way with very little trunk sway, skin artifacts and no significant internal/external rotation of the leg. The root mean square (RMS) errors of the thigh segment orientation measurement were between 2.4 degrees and 4.9 degrees during normal gait that had a 45 degrees flexion/extension range of motion. Measurement error was observed to increase with increasing walking speed probably because of the result of increased trunk sway, axial rotation and skin artifacts. The results show that, without integration and switching between different sensors, using only one kind of sensor, the wearable sensor system is suitable for ambulatory analysis of normal gait orientation of thigh and shank in two directions of the segment-fixed local coordinate system in 3D space. It can then be applied to assess spatio-temporal gait parameters and monitoring the gait function of patients in clinical settings.

New method for assessment of gait variability based on wearable ground reaction force sensor.

In this paper, a new quantitative method of analyzing gait variability using a developed wearable ground reaction force (GRF) sensor system is presented. The design of the sensor system is based on the use of five small 3-axial sensors distributed on the underside of a shoe, so that in human dynamics analysis this system can continuously measure vertical pressure force and bio-directional friction forces referring to anterior-posterior friction force and mediolateral friction force. Compared to existing spatio-temporal evaluation methods using traditional force plates or instrumented treadmills, the new method was developed based on measurements of ambulatory or wearable force sensor which can continuously measure ground reaction force in various environments not limited to the laboratory environment. The area of the center of pressure (CoP) distribution on the foot-plate and the average coefficient of variation of the 3-axial GRF, which correlate strongly with the distribution of CoP, are suggested parameters for quantifying gait variability. To certify the effectiveness of these parameters, we conducted an experimental study on a group of volunteer subjects who walked under a designed experimental protocol.