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Transposable elements (TEs) are the main components of genomes. However, due to their repetitive nature, they are very difficult to study using data obtained with short-read sequencing technologies. Here, we describe an efficient pipeline to accurately recover TE insertion (TEI) sites and sequences from long reads obtained by Oxford Nanopore Technology (ONT) sequencing. With this pipeline, we could precisely describe the landscapes of the most recent TEIs in wild-type strains of Drosophila melanogaster and Drosophila simulans. Their comparison suggests that this subset of TE sequences is more similar than previously thought in these two species. The chromosome assemblies obtained using this pipeline also allowed recovering piRNA cluster sequences, which was impossible using short-read sequencing. Finally, we used our pipeline to analyze ONT sequencing data from a D. melanogaster unstable line in which LTR transposition was derepressed for 73 successive generations. We could rely on single reads to identify new insertions with intact target site duplications. Moreover, the detailed analysis of TEIs in the wild-type strains and the unstable line did not support the trap model claiming that piRNA clusters are hotspots of TE insertions.

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OBJECTIVE: Melanopsin may be involved in the pathophysiology of photophobia in idiopathic isolated blepharospasm. We assessed the efficacy of blocking wavelengths of melanopsin absorption to reduce blinking in blepharospasm as a possible surrogate for photophobia. METHODS: Twenty-one participants (11 blepharospasm and 10 healthy controls) were studied. There were three sessions: (1) a baseline condition to measure the blink rate (BR) without intervention; (2) two conditions where the participants received intermittent light stimuli with high or low intensity without wearing study lenses; (3) four conditions in which the participants received intermittent light stimuli with high intensity while wearing one of four different lenses: tinted lenses with neutral gray or FL-41, or coated lenses that block 480-nm or 590-nm wavelength. The primary outcome measure was the BR. RESULTS: The blepharospasm group blinked more frequently than controls in dim room conditions. Patients reported greater photosensitivity compared to controls based on the questionnaire and exhibited a higher BR with intermittent light stimuli. The BR decreased for both groups when using 480-nm and 590-nm blocking lenses. In the patients, 480-nm and 590-nm blocking lenses reduced the mean BR by 9.6 blink/min and 10.3 blink/min, respectively, while in the control group, the mean BR decreased by 4.4 blink/min and 4.3 blink/min, respectively. CONCLUSIONS: Blepharospasm patients had increased BR with light stimuli which decreased with 590-nm and 480-nm blocking lenses. The 480-nm- and 590-nm- coated lenses might have therapeutic potential in treating photophobia although BR does not appear to be an optimal biomarker for photophobia.

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BACKGROUND: Due to their sessile life style, plant survival is dependent on the ability to build up fast and highly adapted responses to environmental stresses by modulating defense response and organ growth. The phytohormone jasmonate plays an essential role in regulating these plant responses to stress. RESULTS: To assess variation of plant growth responses and identify genetic determinants associated to JA treatment, we conducted a genome-wide association study (GWAS) using an original panel of Vietnamese rice accessions. The phenotyping results showed a high natural genetic variability of the 155 tested rice accessions in response to JA for shoot and root growth. The level of growth inhibition by JA is different according to the rice varieties tested. We conducted genome-wide association study and identified 28 significant associations for root length (RTL), shoot length (SHL), root weight (RTW), shoot weight (SHW) and total weight (TTW) in response to JA treatment. Three common QTLs were found for RTL, RTW and SHL. Among a list of 560 candidate genes found to co-locate with the QTLs, a transcriptome analysis from public database for the JA response allows us to identify 232 regulated genes including several JA-responsive transcription factors known to play a role in stress response. CONCLUSION: Our genome-wide association study shows that common and specific genetic elements are associated with inhibition of shoot and root growth under JA treatment suggesting the involvement of a complex JA-dependent genetic control of rice growth inhibition at the whole plant level. Besides, numerous candidate genes associated to stress and JA response are co-located with the association loci, providing useful information for future studies on genetics and breeding to optimize the growth-defense trade-off in rice.

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We examined whether unilateral exercise creates perception bias in the non-exercised limb and ascertained whether rTMS applied to the primary motor cortex (M1) interferes with this perception. All participants completed 4 interventions: 1) 15-min learning period of intermittent isometric contractions at 35% MVC with the trained hand (EX), 2) 15-min learning period of intermittent isometric contractions at 35% MVC with the trained hand whilst receiving rTMS over the contralateral M1 (rTMS+EX); 3) 15-min of rTMS over the 'trained' M1 (rTMS) and 4) 15-min rest (Rest). Pre and post-interventions, the error of force output production, the perception of effort (RPE), motor evoked potentials (MEPs) and compound muscle action potentials (CMAPs) were measured in both hands. EX did not alter the error of force output production in the trained hand (Δ3%; P>0.05); however, the error of force output production was reduced in the untrained hand (Δ12%; P<0.05). rTMS+EX and rTMS alone did not show an attenuation in the error of force output production in either hand. EX increased RPE in the trained hand (9.1±0.5 vs. 11.3±0.7; P<0.01) but not the untrained hand (8.8±0.6 vs. 9.2±0.6; P>0.05). RPE was significantly higher after rTMS+EX in the trained hand (9.2±0.5 vs. 10.7±0.7; P<0.01) but ratings were unchanged in the untrained hand (8.5±0.6 vs. 9.2±0.5; P>0.05). The novel finding was that exercise alone reduced the error in force output production by over a third in the untrained hand. Further, when exercise was combined with rTMS the transfer of force perception was attenuated. These data suggest that the contralateral M1 of the trained hand might, in part, play an essential role for the transfer of force perception to the untrained hand.

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INTRODUCTION: Chronic unimanual motor practice increases the motor output not only in the trained but also in the nonexercised homologous muscle in the opposite limb. We examined the hypothesis that adaptations in motor cortical excitability of the nontrained primary motor cortex (iM1) and in interhemispheric inhibition from the trained to the nontrained M1 mediate this interlimb cross education. METHODS: Healthy, young volunteers (n=12) performed 1000 submaximal voluntary contractions (MVC) of the right first dorsal interosseus (FDI) at 80% MVC during 20 sessions. RESULTS: Trained FDI's MVC increased 49.9%, and the untrained FDI's MVC increased 28.1%. Although corticospinal excitability in iM1, measured with transcranial magnetic stimulation (TMS) before and after every fifth session, increased 6% at rest, these changes, as those in intracortical inhibition and facilitation, did not correlate with cross education. When weak and strong TMS of iM1 were delivered on a background of a weak and strong muscle contraction, respectively, of the right FDI, excitability of iM1 increased dramatically after 20 sessions. Interhemispheric inhibition decreased 8.9% acutely within sessions and 30.9% chronically during 20 sessions and these chronic reductions progressively became more strongly associated with cross education. There were no changes in force or TMS measures in the trained group's left abductor minimi digiti and there were no changes in the nonexercising control group (n=8). CONCLUSIONS: The findings provide the first evidence for plasticity of interhemispheric connections to mediate cross education produced by a simple motor task.

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BACKGROUND AND PURPOSE: The sequence effect (SE) in Parkinson's disease (PD) denotes progressive slowness in speed or progressive decrease in amplitude of repetitive movements. It is a well-known feature of bradykinesia and is considered unique in PD. Until now, it was well-documented in advanced PD, but not in drug-naïve PD. The aim of this study is to know whether the SE can also be measured in drug-naïve PD. METHODS: We measured the SE with a computer-based, modified Purdue pegboard in 4 drug-naïve PD patients, which matched our previous study with advanced PD patients. RESULTS: We observed progressive slowness during movement, that is, SE. Statistical analysis showed a strong statistical trend toward the SE with the right hand, but no significance with the left hand. There was no statistical significance of SE with either the more or less affected hands. CONCLUSIONS: These results indicate that the SE can be identified in drug-naïve PD, as well as in advanced PD, with objective measurements and support the idea that the SE is a feature in PD observed during the early stage of the disease without medication.

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The sequence effect (SE) in Parkinson's disease (PD) is progressive slowing of sequential movements. It is a feature of bradykinesia, but is separate from a general slowness without deterioration over time. It is commonly seen in PD, but its physiology is unclear. We measured general slowness and the SE separately with a computer-based, modified Purdue pegboard in 11 patients with advanced PD. We conducted a placebo-controlled, four-way crossover study to learn whether levodopa and repetitive transcranial magnetic stimulation (rTMS) could improve general slowness or the SE. We also examined the correlation between the SE and clinical fatigue. Levodopa alone and rTMS alone improved general slowness, but rTMS showed no additive effect on levodopa. Levodopa alone, rTMS alone, and their combination did not alleviate the SE. There was no correlation between the SE and fatigue. This study suggests that dopaminergic dysfunction and abnormal motor cortex excitability are not the relevant mechanisms for the SE. Additionally, the SE is not a component of clinical fatigue. Further work is needed to establish the physiology and clinical relevance of the SE. © 2010 Movement Disorder Society.

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OBJECTIVE: Repetitive transcranial magnetic stimulation (rTMS) has shown promising results in treating Parkinson's disease (PD), but the best values for rTMS parameters are not established. Fifty Hertz rTMS may be superior to 25 Hz rTMS investigated so far. The objective of this study was to determine if 50 Hz rTMS could be delivered safely in PD patients since current safety limits are exceeded. METHODS: Fifty Hertz rTMS was applied with a circular coil on the primary motor cortex (M1). Stimulation intensity was first tested at 60% rest motor threshold [RMT] and 0.5 s train duration and then increased in 0.5 s steps to 2 s, and by 10% steps to 90% RMT. Multi-channel electromyography (EMG) was recorded to control for signs of increasing time-locked EMG activity including correlates of the spread of excitation and after-discharges, or an increase of M1 excitability. Pre- and post-50 Hz rTMS assessments included EEG, Unified Parkinson Disease Rating Scale (UPDRS), Grooved Pegboard Test, Serial Reaction Time Task (SRTT), Folstein Mini-Mental Status Examination (MMSE) and Verbal Fluency to control for motor and cognitive side effects. RESULTS: Ten PD patients were investigated. Multi-channel EMG showed no signs of increased time-locked EMG activity including correlates of the spread of excitation and after-discharges, or increased M1 excitability in 9 patients. A PD patient with bi-temporal spikes in the pre-testing EEG had clinical and EMG correlates of spread of excitation at 90% RMT, but no seizure activity. Pre- and post-50 Hz assessment showed no changes. No adverse events were observed. Fifty Hertz rTMS was well tolerated except by 1 patient who wished to terminate the study due to facial muscle stimulation. CONCLUSION: Fifty Hertz rTMS at an intensity of 90% RMT for 2 s appears safe in patients with PD, but caution should be taken for patients with paroxysmal EEG activity. For this reason, comprehensive screening should include EEG before higher-frequency rTMS is applied. SIGNIFICANCE: This is the first study to investigate safety of 50 Hz rTMS in humans.

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Although there is consensus that the central nervous system mediates the increases in maximal voluntary force (maximal voluntary contraction, MVC) produced by resistance exercise, the involvement of the primary motor cortex (M1) in these processes remains controversial. We hypothesized that 1-Hz repetitive transcranial magnetic stimulation (rTMS) of M1 during resistance training would diminish strength gains. Forty subjects were divided equally into five groups. Subjects voluntarily (Vol) abducted the first dorsal interosseus (FDI) (5 bouts x 10 repetitions, 10 sessions, 4 wk) at 70-80% MVC. Another group also exercised but in the 1-min-long interbout rest intervals they received rTMS [Vol+rTMS, 1 Hz, FDI motor area, 300 pulses/session, 120% of the resting motor threshold (rMT)]. The third group also exercised and received sham rTMS (Vol+Sham). The fourth group received only rTMS (rTMS_only). The 37.5% and 33.3% gains in MVC in Vol and Vol+Sham groups, respectively, were greater (P = 0.001) than the 18.9% gain in Vol+rTMS, 1.9% in rTMS_only, and 2.6% in unexercised control subjects who received no stimulation. Acutely, within sessions 5 and 10, single-pulse TMS revealed that motor-evoked potential size and recruitment curve slopes were reduced in Vol+rTMS and rTMS_only groups and accumulated to chronic reductions by session 10. There were no changes in rMT, maximum compound action potential amplitude (M(max)), and peripherally evoked twitch forces in the trained FDI and the untrained abductor digiti minimi. Although contributions from spinal sources cannot be excluded, the data suggest that M1 may play a role in mediating neural adaptations to strength training.

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In the motor system, one specific movement is generated, and, simultaneously, other possible movements are suppressed; a process called surround inhibition. Focal hand dystonia (FHD) is a movement disorder characterized by a loss of surround inhibition. In order to explain the deficit in surround inhibition induced by volitional movement in FHD patients, we examined the inhibitory circuit activated by afferent stimulation at "long latency". We studied 14 patients (age 48.9+/-13.2 years, 3 females, 11 males) with idiopathic task-related FHD. To measure long-latency afferent inhibition (LAI), transcranial magnetic stimulation (TMS) was applied to the affected hemisphere for FHD patients and to the dominant hemisphere for 17 healthy volunteers. Motor evoked potentials (MEPs) were recorded over abductor digiti minimi (ADM) and first dorsal interosseous (FDI) during rest and during voluntary phasic flexion of the second digit. Subjects were given electrical stimulation to either their fifth digit (homotopic to ADM, heterotopic to FDI) or their second digit (heterotopic to FDI, homotopic to ADM) at twice sensory perceptual threshold 180 ms prior to TMS application. Additionally, F-waves were recorded from ADM. At rest, we found a significant decrease in ADM MEP amplitudes with both homotopic and heterotopic stimulation compared to the corresponding non-stimulated trials. There was a trend toward less LAI in FHD patients. During movement, LAI was significantly decreased in both patients and controls. There was no significant group effect. The results for LAI in FDI were similar to those from ADM. F-wave area in ADM was greater during movement for both homo- and heterotopic stimulation. We found no difference in F-wave area between patients and healthy volunteers. Our results indicate that LAI is unlikely to be an underlying mechanism that contributes to the generation of normal surround inhibition in healthy volunteers or in the disruption of surround inhibition in FHD.

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In patients with focal hand dystonia (FHD), pathological overflow activation occurs in muscles not involved in the movement. Surround inhibition is a neural mechanism that can sharpen desired movement by inhibiting unwanted movement in adjacent muscles. To further establish the phenomenon of surround inhibition and to determine whether short intracortical inhibition (SICI) reflecting inhibition from the local interneurons in primary motor cortex (M1), might play a role in its genesis, single- and paired-pulse transcranial magnetic stimulation (TMS), and Hoffmann reflex testing were applied to evaluate the excitability of the relaxed abductor pollicis brevis muscle (APB) at various intervals during a movement of the index finger in 16 patients with FHD and 20 controls. Whereas controls showed inhibition of APB motor-evoked potential (MEP) size during movement initiation and facilitation of APB MEP size during the maintenance phase, FHD patients did not modulate APB MEP size. In contrast, SICI remained constant in controls, but FHD patients showed reduced SICI during movement initiation. The H(max)/M(max) ratio in control subjects increased during movement initiation. The results provide additional evidence for the presence of surround inhibition in M1, where it occurs only during movement initiation, indicating that different mechanisms underlie movement initiation and maintenance. Thus, surround inhibition is sculpted both in time and space and may be an important neural mechanism during movement initiation to counteract increased spinal excitability. SICI may contribute to its generation, because in patients with FHD, the lack of depression of APB MEP size is accompanied by a reduction in SICI.

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Impaired surround inhibition could account for the abnormal motor control seen in patients with focal hand dystonia, but the neural mechanisms underlying surround inhibition in the motor system are not known. We sought to determine whether an abnormality of the influence of sensory input at short latency could contribute to the deficit of surround inhibition in patients with focal hand dystonia (FHD). To measure digital short afferent inhibition (dSAI), subjects received electrical stimulation at the digit followed after 23 ms by transcranial magnetic stimulation (TMS). Motor evoked potentials (MEPs) were recorded over abductor digiti minimi (ADM) during rest and during voluntary phasic flexion of the second digit. F-waves were also recorded. We studied 13 FHD patients and 17 healthy volunteers. FHD patients had increased homotopic dSAI in ADM during flexion of the second digit, suggesting that this process acts to diminish overflow during movement; this might be a compensatory mechanism. No group differences were observed in first dorsal interosseous. Further, no differences were seen in the F-waves between groups, suggesting that the changes in dSAI are mediated at the cortical level rather than at the spinal cord. Understanding the role of these inhibitory circuits in dystonia may lead to development of therapeutic agents aimed at restoring inhibition.

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During individual finger movement, two opposite phenomena occur at the level of the central nervous system that could affect other intrinsic hand muscle representations, unintentional co-activation, and surround inhibition (SI). At rest, excitability in the motor cortex (M1) is inhibited at about 20 ms after electric stimulation of a peripheral nerve [short-latency afferent inhibition (SAI)]. We sought to determine whether SAI changes during selective index finger movement. Effects were measured by the response to transcranial magnetic stimulation in two functionally distinct target muscles of the hand [abductor digiti minimi muscle (ADM), first dorsal interosseus muscle (FDI)]. An increase in SAI in the ADM during index finger movement compared to at rest could help explain the genesis of SI. Electrical stimulation was applied to either the little finger (homotopic for ADM, heterotopic for FDI) or the index finger (heterotopic for ADM, homotopic for FDI). During index finger movement, homotopic SAI was present only in the ADM, and the effect of peripheral stimulation was greater when there was less co-activation. Heterotopic SAI found at rest disappeared with movement. We conclude that during movement, homotopic SAI on the muscle in the surround of the intended movement may contribute to SI.

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Stimulation of a peripheral nerve of a hand at rest modulates excitability in the motor cortex and, in particular, leads to inhibition when applied at an interval of approximately 200 ms (long-latency afferent inhibition; LAI). Surround inhibition (SI) is the process that inhibits neighboring muscles not involved in a particular task. The neuronal mechanisms of SI are not known, and it is possible that LAI might contribute to it. Using transcranial magnetic stimulation (TMS) with and without movement of the index finger, the motor-evoked potentials (MEPs) were measured of two functionally distinct target muscles of the hand (abductor digiti minimi muscle = ADM, 1st dorsal interosseus muscle = FDI). Electrical stimulation was applied 180 ms before TMS to either the fifth finger or the index finger. Both homotopic and heterotopic finger stimulation resulted in LAI without movement. With index finger movement, motor output further decreased with homo- and heterotopic stimulation in the ADM. In the moving FDI, however, there was no change with either homo- or heterotopic stimulation. Additionally, in the unstimulated movement trials, LAI increased with the amount of unintentional co-activation that occurred despite attempts to maintain the ADM at rest. However, with finger stimulation added, there were almost no increased MEPs despite co-activation. These findings suggest that LAI increases during movement and can enhance SI.

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To investigate the effect of negative motor imagery on corticospinal excitability, we performed transcranial magnetic stimulation (TMS) studies in seven healthy subjects during imagination of suppressing movements. Subjects were asked to imagine suppression of TMS-induced twitching movement of their nondominant left hands by attempting to increase the amount of relaxation after receiving an auditory NoGo cue (negative motor imagery), but to imagine squeezing hands after a Go cue (positive motor imagery). Single- and paired-pulse TMS were triggered at 2 s after Go or NoGo cues. Motor-evoked potentials (MEPs) were recorded in the first dorsal interosseus (FDI), abductor pollicis brevis (APB), and abductor digiti minimi (ADM) muscles of the left hand. Paired-pulse TMS with subthreshold conditioning stimuli at interstimulus intervals of 2 (short intracortical inhibition) and 15 ms (intracortical facilitation) and that with suprathreshold conditioning stimuli at interstimulus interval of 80 ms (long intracortical inhibition) were performed in both negative motor imagery and control conditions. Compared with the control state (no imagination), MEP amplitudes of FDI (but not APB and ADM) were significantly suppressed in negative motor imagery, but those from all three muscles were unchanged during positive motor imagery. F-wave responses (amplitudes and persistence) were unchanged during both negative and positive motor imagery. During negative motor imagery, resting motor threshold was significantly increased, but short and long intracortical inhibition and intracortical facilitation were unchanged. The present results demonstrate that excitatory corticospinal drive is suppressed during imagination of suppressing movements.

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Behavioural studies indicate that a newly acquired motor skill is rapidly consolidated from an initially unstable state to a more stable state, whereas neuroimaging studies demonstrate that the brain engages new regions for performance of the task as a result of this consolidation. However, it is not known where a new skill is retained and processed before it is firmly consolidated. Some early aspects of motor skill acquisition involve the primary motor cortex (M1), but the nature of that involvement is unclear. We tested the possibility that the human M1 is essential to early motor consolidation. We monitored changes in elementary motor behaviour while subjects practised fast finger movements that rapidly improved in movement acceleration and muscle force generation. Here we show that low-frequency, repetitive transcranial magnetic stimulation of M1 but not other brain areas specifically disrupted the retention of the behavioural improvement, but did not affect basal motor behaviour, task performance, motor learning by subsequent practice, or recall of the newly acquired motor skill. These findings indicate that the human M1 is specifically engaged during the early stage of motor consolidation.

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