Relevance of genetic relationship in GWAS and genomic prediction

Abstract

The objective of this study was to analyze the relevance of relationship information on the identification of low heritability quantitative trait loci (QTLs) from a genome-wide association study (GWAS) and on the genomic prediction of complex traits in human, animal and cross-pollinating populations. The simulation-based data sets included 50 samples of 1000 individuals of seven populations derived from a common population with linkage disequilibrium. The populations had non-inbred and inbred progeny structure (50 to 200) with varying number of members (5 to 20). The individuals were genotyped for 10,000 single nucleotide polymorphisms (SNPs) and phenotyped for a quantitative trait controlled by 10 QTLs and 90 minor genes showing dominance. The SNP density was 0.1 cM and the narrow sense heritability was 25%. The QTL heritabilities ranged from 1.1 to 2.9%. We applied mixed model approaches for both GWAS and genomic prediction using pedigree-based and genomic relationship matrices. For GWAS, the observed false discovery rate was kept below the significance level of 5%, the power of detection for the low heritability QTLs ranged from 14 to 50%, and the average bias between significant SNPs and a QTL ranged from less than 0.01 to 0.23 cM. The QTL detection power was consistently higher using genomic relationship matrix. Regardless of population and training set size, genomic prediction provided higher prediction accuracy of complex trait when compared to pedigree-based prediction. The accuracy of genomic prediction when there is relatedness between individuals in the training set and the reference population is much higher than the value for unrelated individuals.

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Exercise Alters Gut Microbiota Composition and Function in Lean and Obese Humans

PURPOSE Exercise is associated with altered gut microbial composition, but studies have not investigated whether the gut microbiota and associated metabolites are modulated by exercise training in humans. We explored the impact of six weeks of endurance exercise on the composition, functional capacity, and metabolic output of the gut microbiota in lean and obese adults with multiple-day dietary controls prior to outcome variable collection. METHODS Thirty-two lean (n=18 [9 female]) and obese (n=14 [11 female]), previously sedentary subjects participated in six weeks of supervised, endurance-based exercise training (3 days/wk) that progressed from 30 to 60 minutes/day and from moderate (60% of heart rate reserve [HRR]) to vigorous intensity (75% HRR). Subsequently, participants subsequently returned to a sedentary lifestyle activity for a six week washout period. Fecal samples were collected before and after six weeks of exercise, as well as after the sedentary washout period, with 3-day dietary controls in place prior to each collection. RESULTS β-diversity analysis revealed that exercise-induced alterations of the gut microbiota were dependent on obesity status. Exercise increased fecal concentrations of short chain fatty acids (SCFAs) in lean, but not obese, participants. Exercise-induced shifts in metabolic output of the microbiota paralleled changes in bacterial genes and taxa capable of SCFA production. Lastly, exercise-induced changes in the microbiota were largely reversed once exercise training ceased. CONCLUSION These findings suggest that exercise training induces compositional and functional changes in the human gut microbiota that are dependent on obesity status, independent of diet and contingent on the sustainment of exercise. Corresponding Author: Jeffrey A. Woods, PhD, 906 S. Goodwin Ave., 348 Louise Freer Hall, University of Illinois at Urbana-Champaign, Urbana IL 61801, Woods1@illinois.edu, 217-244-8815 This work was partially funded by a doctoral student research grant from the American College of Sports Medicine (ACSM). Authors have no professional relationships with companies or manufacturers who will benefit from the results of the present study. Results of the present study do not constitute endorsement by ACSM. Results of the study are presented clearly, honestly and without fabrication, falsification, or inappropriate data manipulation. Accepted for Publication: 6 November 2017 © 2017 American College of Sports Medicine

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Adipose Lipolysis Unchanged by Preexercise Carbohydrate regardless of Glycemic Index

ABSTRACT PURPOSE To determine the impact of pre-exercise carbohydrate of different glycemic indices on subcutaneous abdominal adipose tissue (SCAAT) metabolism and running performance. METHODS Ten trained male runners completed three experimental trials consisting of 30 min at 60% VO2max, 30 min at 75% VO2max, and a 5-km time trial (TT). Thirty min prior to exercise, participants consumed one of three beverages: 1) 75 g low glycemic index modified starch supplement (UCAN), 2) 75 g high glycemic index glucose-based supplement (G), or 3) a flavor-matched non-caloric placebo (PL). SCAAT lipolysis was assessed via microdialysis. RESULTS Prior to exercise, blood glucose and insulin were elevated with G vs. PL (+53.0 ± 21.3 mg[BULLET OPERATOR]dL-1 [SD]; p

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Biological/Genetic Regulation of Physical Activity Level: Consensus from GenBioPAC

ABSTRACT PURPOSE Physical activity unquestionably maintains and improves health; however, physical activity levels globally are low and not rising despite all the resources devoted to this goal. Attention in both the research literature and the public policy domain has focused on social-behavioral factors; however, a growing body of literature suggests that biological determinants play a significant role in regulating physical activity levels. For instance, physical activity level, measured in various manners, has a genetic component in both humans and non-human animal models. This consensus paper, developed as a result of an ACSM-sponsored round table, provides a brief review of the theoretical concepts and existing literature that supports a significant role of genetic and other biological factors in the regulation of physical activity. CONCLUSION Future research on physical activity regulation should incorporate genetics and other biological determinants of physical activity instead of a sole reliance on social and other environmental determinants. Corresponding Author: J. Timothy Lightfoot, Department of Health and Kinesiology, Texas A&M University, College Station, TX, TLightfoot@tamu.edu The results of the present study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. Funding: The authors would like to thank the organizations that provided supporting funds for this Roundtable: The American College of Sports Medicine, The Texas A&M Vice-President of Research office, the Texas A&M Institute for Genome Sciences and Society, The Sydney and JL Huffines Institute of Sports Medicine and Human Performance, and the Omar Smith Endowment. T.G. is supported by NIH/NICHD R21HD084856 and NSF DEB-1655362. M.dH. is supported by project grants from the Swedish Research Council (2015-03657), the Swedish Heart-Lung Foundation (20140543), and NIH (R01DK106236). J.K. is an Academy of Finland funded Research Professor (grants #265240, 263278). Conflict of Interest: The authors report no conflict of interest. The results of the present study do not constitute endorsement by the American College of Sports Medicine. Accepted for Publication: 14 November 2017 © 2017 American College of Sports Medicine

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Strength, Affect Regulation, and Subcortical Morphology in Military Pilots

Introduction Previous studies have shown links of body composition and fitness measures with brain structure, as well as with different aspects of emotional adjustment and well-being. However, the possible role of trait emotion-regulation success in the relationship between fitness/body composition and emotion-related subcortical structures have never been directly addressed Methods 23 elite helicopter pilots were assessed in fat mass percentage, an endurance test to volitional exhaustion, bench-press power output, and negative urgency (trait affect regulation failure). Their brains were scanned using magnetic resonance imaging (MRI) to estimate the size of the accumbens/amygdala complex and the thalamus. Resulting correlations were used to test the relationship between body composition/fitness measures and brain structures' size, and the role of negative urgency therein, using structural equation modelling. Results Fat mass percentage was associated with the size of the thalamus and the amygdala/accumbens complex. In the latter case, negative urgency and bench-press power output predicted structure size (and explained the effect of fat mass percentage away). In other words, bench-press power output and emotion regulation success (but not endurance performance) were associated with a larger amygdala-accumbens size. Conclusion Bench-press power output and emotion regulation success are independently associated with a larger amygdala-accumbens size, although present evidence does not allow determination of causal directionality. Corresponding author: David Cárdenas, Department of Physical Education and Sport, Faculty of Sport Sciences, University of Granada, Carretera de Alfacar s/n, 18011 Granada, Spain. Tel: +34 958244375. Fax: +34 958244369. E-mail: dcardena@ugr.es Research by the first author is funded by a Spanish Ministry of Economy and Competitiveness grant (State Secretariat for Research, Development and Innovation Secretary DEP2013-48211-R), and grant PIN 11 from CEMIX (Centro Mixto UGR-MADOC, Spain). Research by the fourth author is supported by the Spanish Government (Ministerio de Economía y Competitividad, Secretaría de Estado de Invetigación, Desarrollo e Innovación; Convocatoria 2013 de Proyectos I+D de Excelencia), under grant with reference number PSI2013-45055-P (G-Brain). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. No conflicting financial, consultant, institutional, or other interests exist. Results of the present study do not constitute endorsement by the American College of Sports Medicine. Accepted for Publication: 12 November 2017 © 2017 American College of Sports Medicine

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Cardiometabolic Impact of Changing Sitting, Standing, and Stepping in the Workplace

ABSTRACT Background According to cross-sectional and acute experimental evidence, reducing sitting time should improve cardio-metabolic health risk biomarkers. Furthermore, the improvements obtained may depend on whether sitting is replaced with standing or ambulatory activities. Based on data from the Stand Up Victoria multi-component workplace intervention, we examined this issue using compositional data analysis — a method that can examine and compare all activity changes simultaneously. Methods Participants receiving the intervention (n=136 ≥0.6 full-time equivalent desk-based workers, 65% women, mean±SD age=44.6 ±9.1 years from seven worksites) were asked to improve whole-of-day activity by standing up, sitting less and moving more. Their changes in the composition of daily waking hours (activPAL-assessed sitting, standing, stepping) were quantified, then tested for associations with concurrent changes in cardio-metabolic risk (CMR) scores and 14 biomarkers concerning body composition, glucose, insulin and lipid metabolism. Analyses were by mixed models, accounting for clustering (3 months, n=105–120; 12 months, n=80–97). Results Sitting reduction was significantly (p

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SoftHand at the CYBATHLON: a user’s experience

Roughly one-quarter of upper limb prosthesis users reject their prosthesis. Reasons for rejection range from comfort, to cost, aesthetics, function, and more. This paper follows a single user from training wit...

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Using voltage-sensor toxins and their molecular targets to investigate NaV1.8 gating

Abstract

Voltage-gated sodium (Na_V) channel gating is a complex phenomenon which involves a distinct contribution of four integral voltage-sensing domains (VSDI, VSDII, VSDIII, and VSDIV). Utilizing accrued pharmacological and structural insights, we build on an established chimera approach to introduce animal toxin sensitivity in each VSD of an acceptor channel by transferring in portable S3b-S4 motifs from the four VSDs of a toxin-susceptible donor channel (Na_V1.2). By doing so, we observe that in Na_V1.8, a relatively unexplored channel subtype with distinctly slow gating kinetics, VSDI-III participate in channel opening whereas VSDIV can regulate opening as well as fast inactivation. These results illustrate the effectiveness of a pharmacological approach to investigate the mechanism underlying gating of a mammalian Na_V channel complex.

This article is protected by copyright. All rights reserved

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Model of a bilateral Brown-type central pattern generator for symmetric and asymmetric locomotion

The coordinated activity of muscles is produced in part by spinal rhythmogenic neural circuits, termed central pattern generators (CPGs). A classical CPG model is a system of coupled oscillators that transform locomotor drive into coordinated and gait-specific patterns of muscle recruitment. The network properties of this conceptual model can be simulated by a system of ordinary differential equations with a physiologically-inspired coupling locus of interactions capturing the timing relationship for bilateral coordination of limbs in locomotion. While most similar models are solved numerically, it is intriguing to have a full analytical description of this plausible CPG architecture to illuminate the functionality within this structure and to expand it to include steering control. Here, we provided a closed-form analytical solution contrasted against the previous numerical method. The evaluation time of the analytical solution was decreased by an order of magnitude when compared to the numerical approach (relative errors, <0.01%). The analytical solution tested and supported the previous finding that the input to the model can be expressed in units of the desired limb locomotor speed. Furthermore, we performed parametric sensitivity analysis in the context of controlling steering and documented two possible mechanisms associated with either an external drive or intrinsic CPG parameters. The results identify specific propriospinal pathways that may be associated with adaptations within the CPG structure. The model offered several network configurations that may generate the same behavioral outcomes.

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The assessment of neurovascular coupling with the Addenbrooke's Cognitive Examination: a functional Transcranial Doppler Ultrasonographic Study

Cerebrovascular dysfunction occurs early in dementia and can be identified by Transcranial Doppler ultrasonography (TCD). Few studies have examined cerebral blood flow velocity (CBF_v) responses to a detailed cognitive battery. This study aimed to characterise all CBF_v responses, and the effect of hemispheric dominance, to the Addenbrooke's Cognitive Examination (ACE-III) in healthy volunteers. Forty volunteers underwent continuous bilateral TCD, beat-to-beat blood pressure (MAP) (Finapres), heart rate (HR) (electrocardiogram), and end-tidal CO₂ (ETCO₂) (capnography) monitoring. After 5 minutes baseline, all tasks from the ACE-III were performed in 3 sections (A: attention, fluency, memory, B: language, C: visuospatial, memory). Data are population mean normalised percentage (PM%) change from a twenty second baseline period prior to task initiation. Forty bilateral data sets were obtained (27 female, 37 right-hand dominant). All paradigms produced a sharp increase in CBF_v in both dominant (PM% (range): 3.29 to 9.70%), and non-dominant (PM% (range): 4.34 to 11.63%), hemispheres at task initiation, with associated increases in (MAP) (PM% (range): 3.06 to 16.04%). ETCO₂ did not differ significantly at task initiation (PM% (range): -1.1 to 2.4%, p>0.05). HR differed significantly across the A and C tasks at initiation (PM% (range): -1.1 to 2.4%, p<0.05), but not B tasks. In conclusion, all tasks resulted in increases in CBF_v, differing significantly between paradigms. These results require further investigation in a cognitively impaired population.

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Ih Interacts with Somato-Dendritic Structure to Determine Frequency Response to Weak Alternating Electric Field Stimulation

Transcranial current stimulation (tCS) modulates brain dynamics using weak electric fields. Given the pathological changes in brain network oscillations in neurological and psychiatric illnesses, using alternating electric field waveforms that engage rhythmic activity has been proposed as a targeted, network-level treatment approach. Previous studies have investigated the effects of electric fields at the neuronal level. However, the biophysical basis of the cellular response to electric fields has remained limited. Here, we characterized the frequency-dependent response of different compartments in a layer V pyramidal neuron to exogenous electric fields to dissect the relative contributions of voltage-gated ion channels and neuronal morphology. Hyperpolarization-activated cation current (I_h) in the distal dendrites was the primary ionic mechanism shaping the model response to electric field stimulation and caused subthreshold resonance in the tuft at 20 ± 4 Hz. In contrast, subthreshold I_h-mediated resonance in response to local sinusoidal current injection was present in all model compartments at 11 ± 2 Hz. The frequencies of both resonance responses were modulated by I_h conductance density. We found that the difference in resonance frequency between the two stimulation types can be explained by the fact that exogenous electric fields simultaneously polarize the membrane potentials at the distal ends of the neuron (relative to field direction) in opposite directions. Our results highlight the role of I_h in shaping the cellular response to electric field stimulation and suggest that the common model of tCS as a weak somatic current injection fails to capture the cellular effects of electric field stimulation.

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Time course of functional recovery during first three months after surgical transection and repair of nerves to feline soleus and lateral gastrocnemius muscles

Locomotion outcomes after peripheral nerve injury and repair in cats have been described in the literature for the period immediately following the injury (muscle denervation period) and then again for an ensuing period of long-term recovery (at three months and longer) resulting in muscle self-reinnervation. Little is known about the changes in muscle activity and walking mechanics during mid-recovery, i.e. the early reinnervation period that takes place between 5 and 10 weeks of recovery. Here, we investigated hindlimb mechanics and EMG activity of ankle extensors in six cats during level and slope walking before and every two weeks thereafter in a 14-week period of recovery after the soleus (SO) and lateral gastrocnemius (LG) muscle nerves in one hindlimb were surgically transected and repaired. We found that the continued increase in SO and LG EMG magnitudes and corresponding changes in hindlimb mechanics coincided with the formation of neuromuscular synapses revealed in muscle biopsies. Throughout the recovery period, EMG magnitude of SO and LG during the stance phase and the duration of the stance-related activity were load-dependent, similar to those in the intact synergistic medial gastrocnemius and plantaris. These results and the fact that EMG activity of ankle extensors and locomotor mechanics during level and upslope walking recovered 14 weeks after nerve transection and repair suggest that loss of the stretch reflex in self-reinnervated muscles may be compensated by the recovered force-dependent feedback in self-reinnervated muscles, by increased central drive and increased gain in intermuscular motion-dependent pathways from intact ankle extensors.

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Clustering of Heading Selectivity and Perception-Related Activity in the Ventral Intraparietal Area

The ventral intraparietal area (VIP) of the macaque brain is a multimodal cortical region, with many cells tuned to both optic flow and vestibular stimuli. Responses of many VIP neurons also show robust correlations with perceptual judgments during a fine heading discrimination task. Previous studies have shown that heading tuning based on optic flow is represented in a clustered fashion in VIP. However, it is unknown whether vestibular self-motion selectivity is clustered in VIP. Moreover, it is not known whether stimulus- and choice-related signals in VIP show clustering in the context of a heading discrimination task. To address these issues, we compared the response characteristics of isolated single units (SUs) with those of the undifferentiated multiunit (MU) activity corresponding to several neighboring neurons recorded from the same microelectrode. We find that MU activity typically shows selectivity similar to that of simultaneously recorded SUs, for both the vestibular and visual stimulus conditions. In addition, the choice-related activity of MU signals, as quantified using choice-probabilities (CPs), is correlated with the choice-related activity of SUs. Overall, these findings suggest that both sensory and choice-related signals regarding self-motion are clustered in VIP.

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Complementary metrics of human auditory nerve function derived from compound action potentials

Declines in auditory nerve (AN) function contribute to suprathreshold auditory processing and communication deficits in individuals with normal hearing, hearing loss, hyperacusis, and tinnitus. Procedures to characterize AN loss or dysfunction in humans are limited. We report several novel complementary metrics using the compound action potential (CAP), a direct measure of summated AN activity. Together, these metrics may be used to characterize AN function noninvasively in humans. We examined how these metrics change with stimulus intensity, and interpreted these changes within a framework of known physiological properties of the basilar membrane and AN. Our results reveal how neural synchrony and the recruitment of AN fibers with longer first-spike latencies likely contribute to the CAP, affect auditory processing, and differ with noise exposure history in younger adults with normal pure-tone thresholds. Moving forward, this new battery of metrics provides a crucial step towards new diagnostics of AN function in humans.

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Implantable computer-controlled adaptive multi-electrode positioning system (AMEP)

Acute neuronal recordings performed with metal microelectrodes in non-human primates allow investigating the neural substrate of complex cognitive behaviors. Yet, the daily re-insertion and positioning of the electrodes prevents recording from many neurons simultaneously, limiting the suitability of these types of recordings for brain-computer-interface applications or for large-scale population statistical methods on a trial-by-trial basis. In contrast, chronically implanted multi-electrode arrays offer the opportunity to record from many neurons simultaneously, but immovable electrodes prevent optimization of the signal during and after implantation and cause the tissue response to progressively impair the transduced signal quality, thereby limiting the number of different neurons that can be recorded over the lifetime of the implant. Semi-chronically implanted matrices of electrodes, instead, allow individually movable electrodes in depth and achieve higher channel count compared to acute methods, hence partially overcome these limitations. Existing semi-chronic systems with higher channel count lack computerized control of electrode movements, leading to limited user-friendliness and uncertainty in depth-positioning. Here we demonstrate a chronically-implantable Adaptive Multi-Electrode Positioning (AMEP) system with detachable drive for computerized depth-adjustment of individual electrodes over several millimeters. This semi-chronic 16-channel system is designed to optimize the simultaneous yield of units in an extended period following implantation since the electrodes can be independently depth-adjusted with minimal effort and their signal quality continuously assessed. Importantly, the electrode array is designed to remain within a chronic recording chamber for a prolonged time, or can be used for acute recordings with high signal-to-noise ratio in the cerebral cortex of non-human primates.

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Quantitative relations between BOLD responses, cortical energetics and impulse firing

The blood oxygen level dependent (BOLD) functional magnetic resonance imaging (fMRI) signal arises as a consequence of changes in blood flow (CBF) and oxygen usage (CMR$_{O_2}$) that in turn are modulated by changes in neural activity. Much attention has been given to both theoretical and experimental aspects of the energetics but not to the neural activity. Here we identify the best energetic theory for the steady-state BOLD signal on the basis of correct predictions of experimental observations. This theory is then used, together with the recently determined relationship between energetics and neural activity, to predict how the BOLD signal changes with activity. Unlike existing treatments, this new theory incorporates a non-zero baseline activity in a completely consistent way, and is thus able to account for both positive and negative BOLD signals. We also show that the increase in BOLD signal for a given increase in activity is significantly smaller the larger the baseline activity, as is experimentally observed. Furthermore, the decline of the BOLD signal arising from deeper cortical lamina in response to an increase in neural firing is shown to arise as a consequence of the larger baseline activity in deeper lamina. Finally, we provide quantitative relations integrating BOLD responses, energetics and impulse firing, which amongst other predictions, provides the same results as existing theories when the baseline activity is zero.

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Estimating properties of the fast and slow adaptive processes during sensorimotor adaptation

Experience of a prediction error recruits multiple motor learning processes: some that learn strongly from error but have weak retention, some that learn weakly from error but exhibit strong retention. These processes are not generally observable, but are inferred from their collective influence on behavior. Is there a robust way to uncover the hidden processes? A standard approach is to consider a state-space model where the hidden states change following experience of error, and then fit the model to the measured data by minimizing the squared error between measurement and model prediction. We found that this least-squares algorithm (LMSE) often yielded unrealistic predictions about the hidden states, possibly due to its neglect of the stochastic nature of error-based learning. We found that behavioral data during adaptation was better explained by a system in which both error-based learning and movement production were stochastic processes. To uncover the hidden states of learning, we developed a generalized Expectation Maximization (EM) algorithm. In simulation, we found that while LMSE tracked the measured data marginally better than EM, EM was far more accurate in unmasking the timecourses and properties of the hidden states of learning. In a power analysis designed to measure the effect of an intervention on sensorimotor learning, EM significantly reduced the number of subjects that were required for effective hypothesis testing. In summary, we developed a new approach for analysis of data in sensorimotor experiments. The new algorithm improved the ability to uncover the multiple processes that contribute to learning from error.

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Quantitative input: output relationships between human soleus muscle spindle afferents and motoneurons

A method is described which, for the first time, allows instantaneous estimation of the Ia fiber input to human soleus motoneurons following electrical stimulation of the tibial nerve. The basis of the method is to determine the thresholds of the most and least excitable 1a fibers to electrical stimulation, and to treat the intervening thresholds as having a normal distribution about the mean; the validity of this approach is discussed. It was found that, for the same Ia fibre input, the percentage of soleus motoneurons contributing to the H (Hoffmann)-reflex differed considerably among subjects; when the results were pooled, however, there was an approximately linear relationship between Ia input and motoneuron output. Weak extension of the great toe diminished the soleus motoneuron reflex discharge in all but 2 of 16 subjects; the results for weak ankle plantarflexion were less consistent but overall there was a reduction in soleus motoneuron output also. The methodology should provide new insights into disorders of movement and tone, especially as it permits estimates of motoneuron depolarization to be made.

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Effect of Sensory Attenuation on Cortical Movement-Related Oscillations

This study examined the impact of induced sensory deficits on cortical, movement-related oscillations measured using electroencephalography (EEG). We hypothesized that EEG patterns in healthy subjects with induced sensory reduction would be comparable to EEG found after chronic loss of sensory feedback. EEG signals from 64 scalp locations were measured from 10 healthy subjects. Participants dorsiflexed their ankle after prolonged vibration of the tibialis anterior (TA). Beta band time frequency decompositions were calculated using wavelets and compared across conditions. Changes in patterns of movement-related brain activity were observed following attenuation of sensory feedback. A significant decrease in beta power of event related resynchronization was associated with simple ankle dorsiflexion after prolonged vibration of the TA. Attenuation of sensory feedback in young, healthy subjects leads to a corresponding decrease in beta band synchronization. This temporary change in beta oscillations suggests that these modulations are a mechanism for sensorimotor integration. The loss of sensory feedback found in SCI patients contributes to changes in EEG signals underlying motor commands. Similar alterations in cortical signals in healthy subjects with reduced sensory feedback implies these changes reflect normal sensorimotor integration after reduced sensory input rather than brain plasticity.

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Modeling spatial navigation in the presence of dynamic obstacles: a differential games approach

Obstacle circumvention strategies can be shaped by the dynamic interaction of an individual (evader) and an obstacle (pursuer). We have developed a mathematical model with predictive and emergent components, using experimental data from seven healthy young adults walking towards a target while avoiding collision with a stationary or moving obstacle (approaching head-on, or diagonally 30° left or right) in a virtual environment. Two linear properties from the predictive component enable the evader to predict the minimum distance between itself and the obstacle at all times, including the future intersection of trajectories. The emergent component uses the classical differential games model to solve for an optimal circumvention while reaching the target, wherein the locomotor strategy is influenced by the obstacle, target, and the evader velocity. Both model components were fitted to a different set of experimental data obtained from five post-stroke and healthy participants to derive the minimum predicted distance (predictive component) and obstacle influence dimensions (emergent component) during circumvention. Minimum predicted distance between evader and pursuer was kept constant when the evader was closest to the obstacle in all participants. Obstacle influence dimensions varied depending on obstacle approach condition and preferred side of circumvention, reflecting differences in locomotor strategies between post-stroke and healthy individuals. Additionally, important associations between model outputs and observed experimental outcomes were found. The model, supported by experimental data, suggests that both predictive and emergent processes can shape obstacle circumvention strategies in healthy and post-stroke individuals.

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Bayesian Diallel Analysis Reveals Mx1-Dependent and Mx1-Independent Effects on Response to Influenza A Virus in Mice

Influenza A virus (IAV) is a respiratory pathogen that causes substantial morbidity and mortality during both seasonal and pandemic outbreaks. Infection outcomes in unexposed populations are affected by host genetics, but this host genetic architecture is not well understood. Here we obtain a broad view of how heritable factors affect a mouse model of response to IAV infection using an 8x8 diallel of the eight inbred founder strains of the Collaborative Cross (CC). Expanding on a prior statistical framework for modeling treatment response in diallels, we explore how a range of heritable effects modify acute host response to IAV through 4 days post-infection. Heritable effects in aggregate explained about 57% of the variance in IAV-induced weight loss. Much of this was attributable to a pattern of additive effects that became more prominent through day 4 post-infection and was consistent with previous reports of anti-influenza myxovirus resistance 1 (Mx1) polymorphisms segregating between these strains; the additive effects largely recapitulated haplotype effects observed at the Mx1 locus in a previous study of the incipient CC (pre-CC), and are also replicated here in a CC recombinant intercross (CC-RIX) population. Genetic dominance of protective Mx1 haplotypes was observed to differ by subspecies origin: relative to the domesticus null Mx1 allele, musculus acts dominantly whereas castaneus acts additively. After controlling for Mx1, heritable effects, though less distinct, accounted for about 34% of the phenotypic variance. Implications for future mapping studies are discussed.

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Dissecting the Genetic Architecture of Shoot Growth in Carrot (Daucus carota L.) Using a Diallel Mating Design

Carrot production suffers yield losses under weed pressure, and thus improved competitive ability is a breeding priority. However, continued improvement and in-depth genetic studies for these traits relies on knowledge of the underlying genetic architecture. This study estimated heritable and non-heritable components of carrot shoot growth from a diallel mating design using a Bayesian mixed model. Results directly contribute to improvement efforts by ranking hybrids, identifying useful tester lines, and estimating the genetic and non-genetic influences on traits for improved competitive ability in carrot.

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Dependency of Heterochromatin Domains on Replication Factors

Chromatin structure regulates both genome expression and dynamics in eukaryotes where large heterochromatic regions are epigenetically silenced through the methylation of histone H3K9, histone deacetylation, and assembly of repressive complexes. Previous genetic screens with the fission yeast Schizosaccharomyces pombe have led to the identification of key enzymatic activities and structural constituents of heterochromatin. We report here on additional factors discovered by screening a library of deletion mutants for silencing defects at the edge of a heterochromatic domain bound by its natural boundary - the IR-R⁺ element - or by ectopic boundaries. We found that several components of the DNA replication progression complex (RPC) including Mrc1/Claspin, Mcl1/Ctf4, Swi1/Timeless, Swi3/Tipin and the FACT subunit Pob3 are essential to robust heterochromatic silencing, as are the ubiquitin ligase components Pof3 and Def1 that have been implicated in the removal of stalled DNA and RNA polymerases from chromatin. Moreover, the search identified the cohesin release factor Wpl1 and the forkhead protein Fkh2, both likely to function through genome organization, as well as the Ssz1 chaperone, the Fkbp39 proline cis-trans isomerase, that acts on histone H3P30 and P38 in S. cerevisiae, and the chromatin remodeler Fft3. In addition to their effects in the mating-type region, these factors take part in heterochromatic silencing in pericentromeric regions and telomeres, to various extent, revealing for many a general effect in heterochromatin. This list of factors provides precious new clues with which to study the spatio-temporal organization and dynamics of heterochromatic regions in connection with DNA replication.

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Identifying Genetic Differences Between Dongxiang Blue-Shelled and White Leghorn Chickens Using Sequencing Data

The Dongxiang Blue-shelled chicken is one of the most valuable Chinese indigenous poultry breeds. However, compared to the Italian native White Leghorn, although this Chinese breed possesses numerous favorable characteristics, it also exhibits lower growth performance and fertility. We utilize genotyping sequencing data in this paper obtained via genome reduction on a sequencing platform to detect 100,114 single nucleotide polymorphisms (SNPs) and perform further biological analysis and functional annotation. We employed cross-population extended haplotype homozygosity (XP-EHH), EigenGWAS, and efficient mixed-model association eXpedited (EMMAX) methods to detect areas of the genome which are potential selected regions (PSR) in both chicken breeds, and performed gene ontology (GO) enrichment and quantitative trait loci (QTL) analyses annotating using the Kyoto Encyclopedia of Genes and Genomes (KEGG).The results of this study reveal a total of 2,424 outlier loci (p-value<0.01) of which 2,144 occur in the White Leghorn breed and 280 occur in the Dongxiang Blue-shelled chicken. These correspond to 327 and 94 potentially selected regions containing 297 and 54 genes, respectively. The most significantly selected genes in Blue-shelled chicken are TMEM141 and CLIC3, while the SLCO1B3 gene, related to eggshell color, was identified via EigenGWAS. We show that the White Leghorn genes JARID2, RBMS3, GPC3, TRIB2，ROBO1, SAMSN1, OSBP2 and IGFALS are involved in immunity, reproduction, and growth, and thus might represent footprints of the selection process. In contrast, we identified six significantly enriched pathways in the Dongxiang Blue-shelled chicken that are related to amino acid and lipid metabolism as well as signal transduction. Our results also reveal the presence of a GO term associated with cell metabolism that mainly occurs in the White Leghorn breed, while the most significant QTL regions mapped to the Chicken QTL Database (GG_4.0) for the Dongxiang Blue-shelled breed are predominantly related to lesions, bone mineral content and other related traits compared to tibia length and body weight (i.e. at 14 days, 28 days, 42 days, 70 days) in the White Leghorn. The results of this study highlight differences in growth, immunity and egg quality traits between the two breeds and provide a foundation for the exploration of their genetic mechanisms.

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Premature birth affects the degree of airway dysanapsis and mechanical ventilatory constraints

Abstract

Adult survivors of very preterm birth (≤32 weeks gestational age) without (PRE) and with bronchopulmonary dysplasia (BPD) have obstructive lung disease as evidenced by reduced expiratory airflow at rest and have significant mechanical ventilatory constraints during exercise. Airflow obstruction, under any condition, could be due to several factors including small airways. PRE and/or BPD could have smaller airways than their counterparts born at full-term (CON) due to a greater degree of dysanaptic airway development during the pre- and/or post-natal period. Thus, the purpose of the present study was to compare the dysanapsis ratio (DR), as an index of airway size, between PRE, BPD, and CON. To do so, we calculated DR in PRE (n = 21), BPD (n = 14) and CON (n = 34) individuals, as well as examined flow-volume loops at rest and during sub-maximal exercise. DR, using multiple estimates of static recoil pressure, was significantly smaller in PRE and BPD (0.16 ± 0.05 and 0.10 ± 0.03 AU) compared to CON (0.22 ± 0.04 AU; both P < 0.001) and smallest in BPD (P < 0.001). DR was significantly correlated to peak expiratory airflow at rest (r = 0.42; P < 0.001) and the extent of expiratory flow limitation during exercise (r = 0.60; P < 0.001). Our findings suggest that PRE/BPD may have anatomically smaller airways than CON, which may help explain their lower expiratory airflow rate at rest and during exercise and further our understanding of the consequences of preterm birth and neonatal O₂ therapy.

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Effects of platelet-rich plasma on pain and muscle strength in patients with knee osteoarthritis

Objective No studies comparing the effects of platelet-rich plasma (PRP) injection and placebo injection in bilateral knee osteoarthritis (OA) in the same patient, or discussing muscle strength after PRP injection, have been published. Design Twenty patients with bilateral knee OA were eligible, and 40 knees were randomized into two groups: PRP (knees [right or left by a coin toss] receiving a single intra-articular PRP injection) and saline group (the contralateral knee of the same patient, into which single 4-mL intra-articular injection of normal saline was administered). The primary outcome measure was Western Ontario and McMaster's Universities Osteoarthritis Index (WOMAC) and the secondary included isokinetic test results. The evaluation was at baseline and at 2 weeks, 1, 3, and 6 months post-injection. Results The PRP group showed a significant reduction in the WOMAC-pain and -total scores compared to normal saline group (p flexor) was found in the PRP group during a longer follow-up period, PRP treatment resulted in insignificant differences in muscle strength compared to normal saline. Conclusions PRP treatment significantly improves pain, stiffness, and disability in patients with knee OA compared to normal saline treatment. Additional strength training is recommended to enhance muscle strength recovery. Corresponding author: Dr. Liang-Cheng Chen, MD, MS, Department of Physical Medicine and Rehabilitation, Tri-Service General Hospital, School of Medicine, National Defense Medical Center, No. 325, Sec. 2, Cheng-Kung Road, Neihu District, Taipei, Taiwan, Republic of China. E-mail: clctsgh@yahoo.com.tw Sources of Funding: The study is supported by the Ministry of Science and Technology, Taiwan, Republic of China (grant no. MOST 104-2314-B-016-050). Conflict of Interest/Disclosure: There is no Conflict of Interest/Disclosure in this study Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

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The effect of stretching combined with ultrashort wave diathermy on joint function and it’s possible mechanism in a rabbit knee contracture model

Objective The aim of this study was to investigate the therapeutic effect of stretching combined with ultrashort wave on joint contracture and explore its possible mechanism. Design Thirty-two rabbits underwent unilateral immobilization of a knee joint at full extension to cause joint contracture. At 6 weeks after immobilization, the rabbits were randomly divided into four groups: natural recovery group, stretching treatment group, ultrashort wave treatment group and combined treatment group. For comparison, eight control group animals of corresponding age were also examined. The effect of stretching and ultrashort wave treatment on joint contracture was assessed by measuring the joint range of motion (ROM), evaluating the collagen deposition of joint capsule and assessing the mRNA and protein levels for TGF-β1 in the joint capsule. Results The combined treatment group led to the best recovery of joint function. The combined treatment with stretching and ultrashort wave was more effective than stretching or ultrashort wave treatment alone against the synovial thickening of suprapatellar joint capsule, the collagen deposition of anterior joint capsule and the elevated expression of TGF-β1 in the joint capsule. Conclusions Stretching combined with ultrashort wave treatment was effective in improving joint ROM, reducing the biomechanical, histological and molecular manifestations of joint capsule fibrosis in a rabbit model of extending joint contracture. Corresponding author: Yun Zhou. Email:zhouyunanhui@sina.com Author Discosures Conflict of Interest: None. Funding: None. Ethical approval: All procedures performed in this study involving animals were approved by the Institutional Animal Care and Use Committee of Anhui Medical University. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Uranium(VI) sorption complexes on silica in the presence of calcium and carbonate

Publication date: February 2018
Source:Journal of Environmental Radioactivity, Volume 182
Author(s): Alaaeldine Sh. Saleh, Jun-Yeop Lee, Yongheum Jo, Jong-Il Yun
Uranium sorption on minerals and related solids depends to a large degree on its aqueous speciation. The present work attempts to understand the U(VI) sorption behavior on silica under environmentally relevant conditions, i.e. at neutral to weakly alkaline pH and in the presence of dissolved calcium and carbonate. Under these conditions, Ca(UO2)(CO3)3²⁻ and Ca2(UO2)(CO3)3(aq) complexes emerge as the dominant aqueous U(VI) species. The U(VI) sorption affinity was measured as a function of contact time, solution pH, and humic acid. The U(VI) sorption decreased with increase of pH and was not affected by the addition of 50 mg/L humic acid. On the other hand, nitric acid was more effective than EDTA and carbonate at desorbing U(VI). Generally, the U(VI) sorbed on silica at neutral pH was less readily desorbed than that sorbed at higher pH values. Therefore, the U(VI) complex favorably sorbed on silica at the neutral pH is more strongly bound to the silica surface than that sorbed at higher pH values. Time-resolved laser fluorescence spectroscopy confirmed the results of the batch sorption experiments and revealed the presence of two surface U(VI) complexes with fluorescence lifetimes 251 ± 8 μs and 807 ± 24 μs.

Graphical abstract

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Are rehabilitation outcomes after severe anoxic brain injury different from severe traumatic brain injury? A matched case-control study.

Many reports have investigated rehabilitation outcomes after a traumatic brain injury (TBI); however, comparably less is known about whether they differ from outcomes of an anoxic brain injury (ABI). Thus, we aimed to compare the rehabilitation outcomes of patients with ABI with control patients who have TBI. Forty participants with ABI and 40 participants with TBI were included in this retrospective study. Participants with ABI were matched with participants with TBI who had similar clinical characteristics such as age, initial Functional Independence Measurement (FIM) score, and duration of coma. FIM and Functional Ambulation Classification (FAC) scores on rehabilitation admission and on rehabilitation discharge were recorded. The FIM score in the ABI group was 41.7+/-28.5 on rehabilitation admission and increased to 57.1+/-31.4 on rehabilitation discharge. The FIM score in the TBI group was 40.8+/-24.0 on rehabilitation admission and increased to 65.9+/-35.3 on rehabilitation discharge. There was no statistically significant difference in the FIM scores on rehabilitation discharge between groups. Initial FAC was similar in both groups and there was no statistically significant difference in the FAC scores on rehabilitation discharge. The multiple linear regression analysis showed that intensive care unit length of stay had an inverse relationship with the FAC change. We did not find significant differences in the rehabilitation outcomes of participants with ABI compared with participants with TBI. Considering the lack of information in the literature on ABI rehabilitation, this study may be important to guide rehabilitation teams. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Measuring quality of life in individuals with Parkinson's disease attending a self-help club: cross-sectional study in Hungary.

The prevalence of Parkinson's disease (PD) increases with aging. The aim of our cross-sectional study was to measure the quality of life of PD patients attending a self-help 'PD club' and to evaluate the potential positive effect of club life on quality of life. Data collection was carried out using questionnaires (PDQ-39, Hungarian version). Altogether, 101 individuals with clinically diagnosed PD were included, and finally 98 persons' data were analyzed. Among the eight dimensions, the highest score was found in 'bodily discomfort' and the lowest in 'social support'. The overall tendency of the results was similar to another Hungarian study, but the scores in all dimensions were significantly lower in our participants. These positive results seem to correlate with attending the 'PD club', indicating the potential beneficial effect of patients' organizations on promoting mental health. Copyright (C) 2017 Wolters Kluwer Health, Inc. All rights reserved.

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Early signs of cardiovascular dysregulation in young adult binge drinkers

Abstract

Binge drinking is widespread on American college campuses, but its effects on the cardiovascular system are poorly understood. This study sought evidence of preclinical cardiovascular changes in binge drinking young adults (n = 24) compared to nondrinking (n = 24) and social drinking (n = 23) peers during baseline, paced sighing (0.033 Hz), and paced breathing (0.1 Hz) tasks. Binge drinkers showed consistent but often statistically nonsignificant evidence of greater sympathetic activation and reduced baroreflex sensitivity. Interestingly, the structure of group-averaged baseline heart rate spectra was considerably different between groups in the low frequency range (0.05–0.15 Hz). In particular, the binge drinking group–averaged spectra showed several spectral peaks not evident in the other groups, possibly indicating two functionally distinct subranges (0.05–0.08 and 0.08–0.15 Hz) that reflect vascular tone baroreflex activity and heart rate baroreflex activity, respectively. Vascular tone baroreflex gain and power in two peaks in the 0.05–0.08 Hz range were associated with years of drinking in the binge drinking group. Vascular dysfunction may be an early indicator of drinking-related change in the cardiovascular system.

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