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Abstract Background Despite the cardiovascular etiology of stroke, exercise and risk factor modification programs akin to cardiac rehabilitation (CR) are not available. This study aimed to establish the feasibility of adapting a CR model for individuals with mild to moderate stroke disability. A secondary objective was to determine the program's effects on aerobic and walking capacity, and stroke risk factors. Methods A repeated measures design was used with a 3-month baseline period and 6-month adapted CR intervention (n = 43, mean ± SD age 65 ± 12 years, 30 ± 28 months post stroke). Feasibility was determined by the number of participants who completed the study, occurrence of adverse events and frequency, duration and intensity of exercise performed. To determine effectiveness of the program, outcomes measured included aerobic capacity (VO2peak, ventilatory threshold), 6-Minute Walk Test (6MWT) distance, and risk factors. Descriptive statistics characterized the classes attended and number and intensity of exercise sessions. Paired t-tests, one-factor repeated measures analyses of variance contrasts and chi-square analyses were used to compare changes over time. Results Two participants withdrew during the baseline period. Of the remaining 41 participants who commenced the program, 38 (93%) completed all aspects. No serious adverse effects occurred. Post-intervention, VO2peak improved relative to the stable baseline period (P = 0.046) and the increase in ventilatory threshold approached significance (P = 0.062). Conclusions CR is feasible after stroke and may be adapted to accommodate for those with a range of post-stroke disability. It is effective in increasing aerobic capacity. CR may be an untapped opportunity for stroke survivors to access programs of exercise and risk factor modification to lower future event risk. Trial registration ClinicalTrials.gov registration number: NCT01067495

Abstract Background Gait dysfunction and fatigue are common post-stroke, though it is unclear how extended walking activity, as would be performed during activities of daily living, may change over time. The purpose of this study was to examine if spatial and temporal gait variables deteriorate during an extended bout of walking in a test of functional capacity after stroke. Methods 24 community dwelling, independently ambulating individuals greater than 3 months after stroke performed the Six-Minute Walk Test (6MWT). Participants walked over a pressure-sensitive mat on each pass of the 30 m course which recorded spatial and temporal parameters of gait. Mean gait speed and temporal symmetry ratio during each two-minute interval of the 6MWT were examined. Additional post hoc analyses examined the incidence of rests during the 6MWT and changes in gait speed and symmetry. Results On average, participants demonstrated a 3.4 ± 6.5 cm/s decrease in speed over time (p= 0.02). Participants who rested were also characterized by increased asymmetry in the final two minutes (p= 0.05). 30% of participants rested at some point during the test, and if a rest was taken, duration increased in the final two minutes (p= 0.001). Examination of factors which may have been associated with resting indicated that resters had poorer balance (p= 0.006) than non-resting participants. Conclusion This study supports previous findings establishing that walking performance after stroke declines over relatively short bouts of functionally-relevant ambulation. Such changes may be associated with both cardiorespiratory and muscular fatigue mechanisms that influence performance. The findings also indicate that rest duration should be routinely quantified during the 6MWT after stroke, and consequently, further research is necessary to determine how to interpret 6MWT scores when resting occurs.

Abstract Background There is an important need to better understand the activities of individual patients with stroke outside of structured therapy since this activity is likely to have a profound influence on recovery. A case-study approach was used to examine the activity levels and associated physiological load of patients with stroke throughout a day. Methods Activities and physiologic measures were recorded during a continuous 8 hour period from 4 individuals in the sub-acute stage following stroke (ranging from 49 to 80 years old; 4 to 8 weeks post-stroke) in an in-patient rehabilitation hospital. Results Both heart rate (p = 0.0207) and ventilation rate (p < 0.0001) increased as intensity of activity increased. Results revealed individual differences in physiological response to daily activities, and large ranges in physiological response measures during 'moderately' and 'highly' therapeutic activities. Conclusion Activity levels of individuals with stroke during the day were generally low, though task-related changes in physiologic measures were observed. Large variability in the physiological response to even the activities deemed to be greatest intensity suggests that inclusion of such extended measurement of physiologic measures may improve understanding of physiological profile that could guide elements of the physical therapy prescription.

Abstract Background and purpose The Six-Minute Walk Test (6MWT) has been employed as a measure of functional capacity, but its relationship to cardiorespiratory fitness in stroke is not well established. Gait speed measured over short distances is commonly used as an index of walking competency following stroke. We evaluated the relationship between the 6MWT, aerobic fitness (VO2peak) and walking competency in sub-acute stroke. Methods Thirty-six individuals (mean age ± SD, 64.6 ± 14.4 years; time post-stroke 16.2 ± 13.3 days) were evaluated using the 6MWT (distance, speed, heart rate), a maximal exercise test (VO2peak, heart rate, exercise test duration), and walking competency using a five meter walk (speed, symmetry ratio). Correlation analyses were used to examine the relationships between these outcomes. Results There was a strong correlation between the 6MWT and five meter walk velocity for preferred (r = 0.79) and fast (r = 0.82) speed (p < 0.001). On average, the 6MWT speed was faster than the preferred gait speed (94.9 cm/s vs. 83.8 cm/s, p = 0.003), but slower than the fast-paced walk (115.1 cm/s, p < 0.001). There was significant though more moderate association between 6MWT distance and VO2peak (r = 0.56, p < 0.001) and exercise test duration (r = 0.60, p < 0.001). Conclusion The speed selected during the 6MWT was strongly related to the velocities selected during the five meter walk distance (intermediate to the selected preferred and fast speeds). Although the 6MWT may be challenging to the cardiorespiratory system, it appears to be more strongly influenced by potential limits to walking speed rather than cardiorespiratory capacity. As a result, this test is not, by itself, an adequate measure of aerobic fitness early after stroke.

Background: RNA-seq has brought forth significant discoveries regarding aberrations in RNA processing, implicating these RNA variants in a variety of diseases. Aberrant splicing and single nucleotide variants (SNVs) in RNA have been demonstrated to alter transcript stability, localization, and function. In particular, the upregulation of ADAR, an enzyme that mediates adenosine-to-inosine editing, has been previously linked to an increase in the invasiveness of lung adenocarcinoma cells and associated with splicing regulation. Despite the functional importance of studying splicing and SNVs, the use of short-read RNA-seq has limited the community's ability to interrogate both forms of RNA variation simultaneously., Results: We employ long-read sequencing technology to obtain full-length transcript sequences, elucidating cis-effects of variants on splicing changes at a single molecule level. We develop a computational workflow that augments FLAIR, a tool that calls isoform models expressed in long-read data, to integrate RNA variant calls with the associated isoforms that bear them. We generate nanopore data with high sequence accuracy from H1975 lung adenocarcinoma cells with and without knockdown of ADAR. We apply our workflow to identify key inosine isoform associations to help clarify the prominence of ADAR in tumorigenesis., Conclusions: Ultimately, we find that a long-read approach provides valuable insight toward characterizing the relationship between RNA variants and splicing patterns., (© 2024. The Author(s).)

The Long-read RNA-Seq Genome Annotation Assessment Project Consortium was formed to evaluate the effectiveness of long-read approaches for transcriptome analysis. Using different protocols and sequencing platforms, the consortium generated over 427 million long-read sequences from complementary DNA and direct RNA datasets, encompassing human, mouse and manatee species. Developers utilized these data to address challenges in transcript isoform detection, quantification and de novo transcript detection. The study revealed that libraries with longer, more accurate sequences produce more accurate transcripts than those with increased read depth, whereas greater read depth improved quantification accuracy. In well-annotated genomes, tools based on reference sequences demonstrated the best performance. Incorporating additional orthogonal data and replicate samples is advised when aiming to detect rare and novel transcripts or using reference-free approaches. This collaborative study offers a benchmark for current practices and provides direction for future method development in transcriptome analysis., (© 2024. The Author(s).)

Repetitive transcranial magnetic stimulation (rTMS) has become an increasingly popular tool to modulate neural excitability and induce neural plasticity in clinical and preclinical models; however, the physiological mechanisms in which it exerts these effects remain largely unknown. To date, studies have primarily focused on characterizing rTMS-induced changes occurring at the synapse, with little attention given to changes in intrinsic membrane properties. However, accumulating evidence suggests that rTMS may induce its effects, in part, via intrinsic plasticity mechanisms, suggesting a new and potentially complementary understanding of how rTMS alters neural excitability and neural plasticity. In this review, we provide an overview of several intrinsic plasticity mechanisms before reviewing the evidence for rTMS-induced intrinsic plasticity. In addition, we discuss a select number of neurological conditions where rTMS-induced intrinsic plasticity has therapeutic potential before speculating on the temporal relationship between rTMS-induced intrinsic and synaptic plasticity., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Burn injuries are devastating traumas, often leading to life-long consequences that extend beyond the observable burn scar. In the context of the nervous system, burn injury patients commonly develop chronic neurological disorders and have been suggested to have impaired motor cortex function, but the long-lasting impact on neurons and glia in the brain is unknown. Using a mouse model of non-severe burn injury, excitatory and inhibitory neurons in the primary motor cortex were labelled with fluorescent proteins using adeno-associated viruses (AAVs). A total of 5 weeks following the burn injury, virus labelled excitatory and inhibitory neurons were isolated using fluorescence-activated cell sorting (FACS). In addition, microglia and astrocytes from the remaining cortical tissue caudal to the motor cortex were immunolabelled and isolated with FACS. Whole transcriptome RNA-sequencing was used to identify any long-lasting changes to gene expression in the different cell types. RNA-seq analysis showed changes to the expression of a small number of genes with known functions in excitatory neurons and microglia, but not in inhibitory neurons or astrocytes. Specifically, genes related to GABA-A receptors in excitatory neurons and several cellular functions in microglia were found to be downregulated in burn injured mice. These findings suggest that non-severe burn injuries lead to long lasting transcriptomic changes in the brain, but only in specific cell types. Our findings provide a broad overview of the long-lasting impact of burn injuries on the central nervous system which may help identify potential therapeutic targets to prevent neurological dysfunction in burn patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Ong, Beros, Fuller, Wood, Melton, Rodger, Fear, Barrett, Stevenson and Tang.)

Static magnetic stimulation (SMS) is a form of non-invasive brain stimulation that alters neural activity and induces neural plasticity that outlasts the period of stimulation. This can modify corticospinal excitability or motor behaviours, suggesting that SMS may alter the intrinsic excitability of neurons. In mammalian neurons, the axon initial segment (AIS) is the site of action potential initiation and undergoes structural plasticity (changes in length and position from the soma) as a homeostatic mechanism to counteract chronic changes in neuronal activity. We investigated whether the chronic application of SMS (6 and 48 h, 0.5 T) induces structural AIS plasticity in postnatally derived primary cortical neurons. Following 6 h of SMS, we observed a shortening in mean AIS length compared to control, that persisted 24 h post stimulation. In contrast, 48 h of SMS induced an immediate distal shift that persisted 24 h post-stimulation. Pharmacological blockade of voltage gated L/T-type calcium channels during stimulation did not prevent SMS-induced AIS structural plasticity. Our findings provide the foundation to expand the use of chronic SMS as a non-invasive method to promote AIS plasticity., (© 2024. The Author(s).)

Lenses with a tunable focus are highly desirable but remain a challenge. Here, we demonstrate a microwave varifocal meta-lens based on the Alvarez lens principle, consisting of two mechanically movable tri-layer metasurface phase plates with reversed cubic spatial profiles. The manufactured multilayer Alvarez meta-lens enables microwave beam collimation/focusing at frequencies centered at 7.5 GHz, and shows one octave focal length tunability when transversely translating the phase plates by 8 cm. The measurements reveal a gain enhancement up to 15 dB, 3-dB beam width down to 3.5 ∘ , and relatively broad 3-dB bandwidth of 3 GHz. These advantageous characteristics, along with its simplicity, compactness, and lightweightness, make the demonstrated flat Alvarez meta-lens suitable for deployment in many microwave systems.

U2AF1 is one of the most recurrently mutated splicing factors in lung adenocarcinoma and has been shown to cause transcriptome-wide pre-mRNA splicing alterations; however, the full-length altered mRNA isoforms associated with the mutation are largely unknown. To better understand the impact U2AF1 has on full-length isoform fate and function, we conducted high-throughput long-read cDNA sequencing from isogenic human bronchial epithelial cells with and without a U2AF1 S34F mutation. We identified 49,366 multi-exon transcript isoforms, more than half of which did not match GENCODE or short-read-assembled isoforms. We found 198 transcript isoforms with significant expression and usage changes relative to WT, only 68% of which were assembled by short reads. Expression of isoforms from immune-related genes is largely down-regulated in mutant cells and without observed splicing changes. Finally, we reveal that isoforms likely targeted by nonsense-mediated decay are down-regulated in U2AF1 S34F cells, suggesting that isoform changes may alter the translational output of those affected genes. Altogether, our work provides a resource of full-length isoforms associated with U2AF1 S34F in lung cells., (© 2023 Soulette et al.)

Objective . Noninvasive focal stimulation of deep brain regions has been a major goal for neuroscience and neuromodulation in the past three decades. Transcranial magnetic stimulation (TMS), for instance, cannot target deep regions in the brain without activating the overlying tissues and has poor spatial resolution. In this manuscript, we propose a new concept that relies on the temporal interference (TI) of two high-frequency magnetic fields generated by two electromagnetic solenoids. Approach . To illustrate the concept, custom solenoids were fabricated and optimized to generate temporal interfering electric fields for rodent brain stimulation. C-Fos expression was used to track neuronal activation. Main result . C-Fos expression was not present in regions impacted by only one high-frequency magnetic field indicating ineffective recruitment of neural activity in non-target regions. In contrast, regions impacted by two fields that interfere to create a low-frequency envelope display a strong increase in c-Fos expression. Significance . Therefore, this magnetic temporal interference solenoid-based system provides a framework to perform further stimulation studies that would investigate the advantages it could bring over conventional TMS systems., (© 2023 IOP Publishing Ltd.)

Alternative splicing generates distinct mRNA variants and is essential for development, homeostasis, and renewal. Proteins of the serine/arginine (SR)-rich splicing factor family are major splicing regulators that are broadly required for organ development as well as cell and organism viability. However, how these proteins support adult organ function remains largely unknown. Here, we used the continuously growing mouse incisor as a model to dissect the functions of the prototypical SR family protein SRSF1 during tissue homeostasis and renewal. We identified an SRSF1-governed alternative splicing network that is specifically required for dental proliferation and survival of progenitors but dispensable for the viability of differentiated cells. We also observed a similar progenitor-specific role of SRSF1 in the small intestinal epithelium, indicating a conserved function of SRSF1 across adult epithelial tissues. Thus, our findings define a regulatory mechanism by which SRSF1 specifically controls progenitor-specific alternative splicing events to support adult tissue homeostasis and renewal., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The butterfly optimization algorithm (BOA) is a swarm-based metaheuristic algorithm inspired by the foraging behaviour and information sharing of butterflies. BOA has been applied to various fields of optimization problems due to its performance. However, BOA also suffers from drawbacks such as diminished population diversity and the tendency to get trapped in local optimum. In this paper, a hybrid butterfly optimization algorithm based on a Gaussian distribution estimation strategy, called GDEBOA, is proposed. A Gaussian distribution estimation strategy is used to sample dominant population information and thus modify the evolutionary direction of butterfly populations, improving the exploitation and exploration capabilities of the algorithm. To evaluate the superiority of the proposed algorithm, GDEBOA was compared with six state-of-the-art algorithms in CEC2017. In addition, GDEBOA was employed to solve the UAV path planning problem. The simulation results show that GDEBOA is highly competitive., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Huan Zhou et al.)

Slime mould algorithm (SMA) is a population-based metaheuristic algorithm inspired by the phenomenon of slime mould oscillation. The SMA is competitive compared to other algorithms but still suffers from the disadvantages of unbalanced exploitation and exploration and is easy to fall into local optima. To address these shortcomings, an improved variant of SMA named MSMA is proposed in this paper. Firstly, a chaotic opposition-based learning strategy is used to enhance population diversity. Secondly, two adaptive parameter control strategies are proposed to balance exploitation and exploration. Finally, a spiral search strategy is used to help SMA get rid of local optimum. The superiority of MSMA is verified in 13 multidimensional test functions and 10 fixed-dimensional test functions. In addition, two engineering optimization problems are used to verify the potential of MSMA to solve real-world optimization problems. The simulation results show that the proposed MSMA outperforms other comparative algorithms in terms of convergence accuracy, convergence speed, and stability., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 An-Di Tang et al.)

Background: Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive tool commonly used to drive neural plasticity in the young adult and aged brain. Recent data from mouse models have shown that even at subthreshold intensities (0.12 T), rTMS can drive neuronal and glial plasticity in the motor cortex. However, the physiological mechanisms underlying subthreshold rTMS induced plasticity and whether these are altered with normal ageing are unclear., Objective: To assess the effect of subthreshold rTMS, using the intermittent theta burst stimulation (iTBS) protocol on structural synaptic plasticity in the mouse motor cortex of young and aged mice., Methods: Longitudinal in vivo 2-photon microscopy was used to measure changes to the structural plasticity of pyramidal neuron dendritic spines in the motor cortex following a single train of subthreshold rTMS (in young adult and aged animals) or the same rTMS train administered on 4 consecutive days (in young adult animals only). Data were analysed with Bayesian hierarchical generalized linear regression models and interpreted with the aid of Bayes Factors (BF)., Results: We found strong evidence (BF > 10) that subthreshold rTMS altered the rate of dendritic spine losses and gains, dependent on the number of stimulation sessions and that a single session of subthreshold rTMS was effective in driving structural synaptic plasticity in both young adult and aged mice., Conclusion: These findings provide further evidence that rTMS drives synaptic plasticity in the brain and uncovers structural synaptic plasticity as a key mechanism of subthreshold rTMS induced plasticity., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest, including any financial or personal relationship with other people or organisations that could inappropriately influence our work., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Carbon nanotubes (CNTs) reinforced aluminum matrix nanocomposites were fabricated by Accumulative Roll Bonding (ARB). The surface morphologies, mechanical properties, grains texture and orientation of the Al/CNTs nanocomposites were characterized, and the mechanisms and influences of CNTs contents and ARB cycles on the mechanical performance and grain textures of Al/CNTs were investigated and revealed. The strength of the composites rose with increase of the CNTs content, and the ARB cycles showed a 26% improvement when the CNTs content varied from 0 to 1 volume percent (vol.%). The increase in the mass fraction of the carbon nanotubes made the grain distribution in the Al/CNTs nanocomposite samples more diffuse. Besides, the stable texture of the hot rolled crystal grains on the α orientation are constantly turning to {011}< 011> with the mass fraction of the reinforcing phase increased.

The unmanned aerial vehicle (UAV) path planning problem is a type of complex multi-constraint optimization problem that requires a reasonable mathematical model and an efficient path planning algorithm. In this paper, the fitness function including fuel consumption cost, altitude cost, and threat cost is established. There are also four set constraints including maximum flight distance, minimum flight altitude, maximum turn angle, and maximum climb angle. The constrained optimization problem is transformed into an unconstrained optimization problem by using the penalty function introduced. To solve the model, a multiple population hybrid equilibrium optimizer (MHEO) is proposed. Firstly, the population is divided into three subpopulations based on fitness and different strategies are executed separately. Secondly, a Gaussian distribution estimation strategy is introduced to enhance the performance of MHEO by using the dominant information of the populations to guide the population evolution. The equilibrium pool is adjusted to enhance population diversity. Furthermore, the Lévy flight strategy and the inferior solution shift strategy are used to help the algorithm get rid of stagnation. The CEC2017 test suite was used to evaluate the performance of MHEO, and the results show that MHEO has a faster convergence speed and better convergence accuracy compared to the comparison algorithms. The path planning simulation experiments show that MHEO can steadily and efficiently plan flight paths that satisfy the constraints, proving the superiority of the MHEO algorithm while verifying the feasibility of the path planning model.

Central nervous system myelination increases action potential conduction velocity. However, it is unclear how myelination is coordinated to ensure the temporally precise arrival of action potentials and facilitate information processing within cortical and associative circuits. Here, we show that myelin sheaths, supported by mature oligodendrocytes, remain plastic in the adult mouse brain and undergo subtle structural modifications to influence action potential conduction velocity. Repetitive transcranial magnetic stimulation and spatial learning, two stimuli that modify neuronal activity, alter the length of the nodes of Ranvier and the size of the periaxonal space within active brain regions. This change in the axon-glial configuration is independent of oligodendrogenesis and robustly alters action potential conduction velocity. Because aptitude in the spatial learning task was found to correlate with action potential conduction velocity in the fimbria-fornix pathway, modifying the axon-glial configuration may be a mechanism that facilitates learning in the adult mouse brain., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Repetitive transcranial magnetic stimulation (rTMS) is a form of non-invasive brain stimulation frequently used to induce neuroplasticity in the brain. Even at low intensities, rTMS has been shown to modulate aspects of neuronal plasticity such as motor learning and structural reorganisation of neural tissue. However, the impact of low intensity rTMS on glial cells such as astrocytes remains largely unknown. This study investigated changes in RNA (qPCR array: 125 selected genes) and protein levels (immunofluorescence) in cultured mouse astrocytes following a single session of low intensity repetitive magnetic stimulation (LI-rMS - 18 mT). Purified neonatal cortical astrocyte cultures were stimulated with either 1Hz (600 pulses), 10Hz (600 or 6000 pulses) or sham (0 pulses) LI-rMS, followed by RNA extraction at 5 h post-stimulation, or fixation at either 5 or 24-h post-stimulation. LI-rMS resulted in a two-to-four-fold downregulation of mRNA transcripts related to calcium signalling (Stim1 and Orai3), inflammatory molecules (Icam1) and neural plasticity (Ncam1). 10Hz reduced expression of Stim1, Orai3, Kcnmb4, and Ncam1 mRNA, whereas 1Hz reduced expression of Icam1 mRNA and signalling-related genes. Protein levels followed a similar pattern for 10Hz rMS, with a significant reduction of STIM1, ORAI3, KCNMB4, and NCAM1 protein compared to sham, but 1Hz increased STIM1 and ORAI3 protein levels relative to sham. These findings demonstrate the ability of 1Hz and 10Hz LI-rMS to modulate specific aspects of astrocytic phenotype, potentially contributing to the known effects of low intensity rTMS on excitability and neuroplasticity., Competing Interests: Declaration of competing interest The authors declare no competing interest., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

While splicing changes caused by somatic mutations in SF3B1 are known, identifying full-length isoform changes may better elucidate the functional consequences of these mutations. We report nanopore sequencing of full-length cDNA from CLL samples with and without SF3B1 mutation, as well as normal B cell samples, giving a total of 149 million pass reads. We present FLAIR (Full-Length Alternative Isoform analysis of RNA), a computational workflow to identify high-confidence transcripts, perform differential splicing event analysis, and differential isoform analysis. Using nanopore reads, we demonstrate differential 3' splice site changes associated with SF3B1 mutation, agreeing with previous studies. We also observe a strong downregulation of intron retention events associated with SF3B1 mutation. Full-length transcript analysis links multiple alternative splicing events together and allows for better estimates of the abundance of productive versus unproductive isoforms. Our work demonstrates the potential utility of nanopore sequencing for cancer and splicing research.

High-throughput complementary DNA sequencing technologies have advanced our understanding of transcriptome complexity and regulation. However, these methods lose information contained in biological RNA because the copied reads are often short and modifications are not retained. We address these limitations using a native poly(A) RNA sequencing strategy developed by Oxford Nanopore Technologies. Our study generated 9.9 million aligned sequence reads for the human cell line GM12878, using thirty MinION flow cells at six institutions. These native RNA reads had a median length of 771 bases, and a maximum aligned length of over 21,000 bases. Mitochondrial poly(A) reads provided an internal measure of read-length quality. We combined these long nanopore reads with higher accuracy short-reads and annotated GM12878 promoter regions to identify 33,984 plausible RNA isoforms. We describe strategies for assessing 3' poly(A) tail length, base modifications and transcript haplotypes.

Although electromagnetic brain stimulation is a promising treatment in neurology and psychiatry, clinical outcomes are variable, and underlying mechanisms are ill-defined, which impedes the development of new effective stimulation protocols. Here, we show, in vivo and ex vivo, that repetitive transcranial magnetic stimulation at low-intensity (LI-rTMS) induces axon outgrowth and synaptogenesis to repair a neural circuit. This repair depends on stimulation pattern, with complex biomimetic patterns being particularly effective, and the presence of cryptochrome, a putative magnetoreceptor. Only repair-promoting LI-rTMS patterns up-regulated genes involved in neuronal repair; almost 40% of were cryptochrome targets. Our data open a new framework to understand the mechanisms underlying structural neuroplasticity induced by electromagnetic stimulation. Rather than neuronal activation by induced electric currents, we propose that weak magnetic fields act through cryptochrome to activate cellular signaling cascades. This information opens new routes to optimize electromagnetic stimulation and develop effective treatments for different neurological diseases., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)

Neuronal activity is a potent extrinsic regulator of oligodendrocyte generation and central nervous system myelination. Clinically, repetitive transcranial magnetic stimulation (rTMS) is delivered to noninvasively modulate neuronal activity; however, the ability of rTMS to facilitate adaptive myelination has not been explored. By performing cre-lox lineage tracing, to follow the fate of oligodendrocyte progenitor cells in the adult mouse brain, we determined that low intensity rTMS (LI-rTMS), administered as an intermittent theta burst stimulation, but not as a continuous theta burst or 10 Hz stimulation, increased the number of newborn oligodendrocytes in the adult mouse cortex. LI-rTMS did not alter oligodendrogenesis per se, but instead increased cell survival and enhanced myelination. These data suggest that LI-rTMS can be used to noninvasively promote myelin addition to the brain, which has potential implications for the treatment of demyelinating diseases such as multiple sclerosis., (© 2019 Wiley Periodicals, Inc.)

Response inhibition, the ability to withhold a dominant and prepotent response following a change in circumstance or sensory stimuli, declines with advancing age. While non-invasive brain stimulation (NiBS) has shown promise in alleviating some cognitive and motor functions in healthy older individuals, NiBS research focusing on response inhibition has mostly been conducted on younger adults. These extant studies have primarily focused on modulating the activity of distinct neural regions known to be critical for response inhibition, including the right inferior frontal gyrus (rIFG) and the pre-supplementary motor area (pre-SMA). However, given that changes in structural and functional connectivity have been associated with healthy aging, this review proposes that NiBS protocols aimed at modulating the functional connectivity between the rIFG and pre-SMA may be the most efficacious approach to investigate-and perhaps even alleviate-age-related deficits in inhibitory control., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Repetitive transcranial magnetic stimulation (rTMS) is commonly used to modulate cortical plasticity in clinical and non-clinical populations. Clinically, rTMS is delivered to targeted regions of the cortex at high intensities (>1 T). We have previously shown that even at low intensities, rTMS induces structural and molecular plasticity in the rodent cortex. To determine whether low intensity rTMS (LI-rTMS) alters behavioural performance, daily intermittent theta burst LI-rTMS (120 mT) or sham was delivered as a priming or consolidating stimulus to mice completing 10 consecutive days of skilled reaching training. Relative to sham, priming LI-rTMS (before each training session), increased skill accuracy (~9%) but did not alter the rate of learning over time. In contrast, consolidating LI-rTMS (after each training session), resulted in a small increase in the rate of learning (an additional ~1.6% each day) but did not alter the daily skill accuracy. Changes in behaviour with LI-rTMS were not accompanied with long lasting changes in brain-derived neurotrophic factor (BDNF) expression or in the expression of plasticity markers at excitatory and inhibitory synapses for either priming or consolidation groups. These results suggest that LI-rTMS can alter specific aspects of skilled motor learning in a manner dependent on the timing of intervention.

Tinnitus (phantom auditory perception associated with hearing loss) can seriously affect wellbeing. Its neural substrate is unknown however it has been linked with abnormal activity in auditory pathways. Though no cure currently exists, repetitive transcranial magnetic stimulation (rTMS) has been shown to reduce tinnitus in some patients, possibly via induction of cortical plasticity involving brain derived neurotrophic factor (BDNF). We examined whether low intensity rTMS (LI-rTMS) alleviates signs of tinnitus in a guinea pig model and whether this involves changes in BDNF expression and hyperactivity in inferior colliculus. Acoustic trauma was used to evoke hearing loss, central hyperactivity and tinnitus. When animals developed tinnitus, treatment commenced (10 sessions of 10 minutes 1 Hz LI-rTMS or sham over auditory cortex over 14 days). After treatment ceased animals were tested for tinnitus, underwent single-neuron recordings in inferior colliculus to assess hyperactivity and samples from cortex and inferior colliculus were taken for BDNF ELISA. Analysis revealed a significant reduction of tinnitus after LI-rTMS compared to sham, without a statistical significant effect on BDNF levels or hyperactivity. This suggests that LI-rTMS alleviates behavioural signs of tinnitus by a mechanism independent of inferior colliculus hyperactivity and BDNF levels and opens novel therapeutic avenues for tinnitus treatment.

Repetitive transcranial magnetic stimulation (rTMS) has become a popular method of modulating neural plasticity in humans. Clinically, rTMS is delivered at high intensities to modulate neuronal excitability. While the high-intensity magnetic field can be targeted to stimulate specific cortical regions, areas adjacent to the targeted area receive stimulation at a lower intensity and may contribute to the overall plasticity induced by rTMS. We have previously shown that low-intensity rTMS induces molecular and structural plasticity in vivo, but the effects on membrane properties and neural excitability have not been investigated. Here we investigated the acute effect of low-intensity repetitive magnetic stimulation (LI-rMS) on neuronal excitability and potential changes on the passive and active electrophysiological properties of layer 5 pyramidal neurons in vitro. Whole-cell current clamp recordings were made at baseline prior to subthreshold LI-rMS (600 pulses of iTBS, n=9 cells from 7 animals) or sham (n=10 cells from 9 animals), immediately after stimulation, as well as 10 and 20min post-stimulation. Our results show that LI-rMS does not alter passive membrane properties (resting membrane potential and input resistance) but hyperpolarises action potential threshold and increases evoked spike-firing frequency. Increases in spike firing frequency were present throughout the 20min post-stimulation whereas action potential (AP) threshold hyperpolarization was present immediately after stimulation and at 20min post-stimulation. These results provide evidence that LI-rMS alters neuronal excitability of excitatory neurons. We suggest that regions outside the targeted region of high-intensity rTMS are susceptible to neuromodulation and may contribute to rTMS-induced plasticity., (Copyright © 2016 IBRO. All rights reserved.)

Repetitive transcranial magnetic stimulation (rTMS) is primarily used in humans to change the state of corticospinal excitability. To assess the efficacy of different rTMS stimulation protocols, motor evoked potentials (MEPs) are used as a readout due to their non-invasive nature. Stimulation of the motor cortex produces a response in a targeted muscle, and the amplitude of this twitch provides an indirect measure of the current state of the cortex. When applied to the motor cortex, rTMS can alter MEP amplitude, however, results are variable between participants and across studies. In addition, the mechanisms underlying any change and its locus are poorly understood. In order to better understand these effects, MEPs have been investigated in vivo in animal models, primarily in rats. One major difference in protocols between rats and humans is the use of general anesthesia in animal experiments. Anesthetics are known to affect plasticity-like mechanisms and so may contaminate the effects of an rTMS protocol. In the present study, we explored the effect of anesthetic on MEP amplitude, recorded before and after intermittent theta burst stimulation (iTBS), a patterned rTMS protocol with reported facilitatory effects. MEPs were assessed in the brachioradialis muscle of the upper forelimb under two anesthetics: a xylazine/zoletil combination and urethane. We found MEPs could be induced under both anesthetics, with no differences in the resting motor threshold or the average baseline amplitudes. However, MEPs were highly variable between animals under both anesthetics, with the xylazine/zoletil combination showing higher variability and most prominently a rise in amplitude across the baseline recording period. Interestingly, application of iTBS did not facilitate MEP amplitude under either anesthetic condition. Although it is important to underpin human application of TMS with mechanistic examination of effects in animals, caution must be taken when selecting an anesthetic and in interpreting results during prolonged TMS recording.

Cr-MnOx/cordierite composites were prepared by Sol-gel, Impregnation, Co-precipitation and Rheological phase reaction method. Various technologies including X-ray diffraction (XRD), scanning electron microscopy (SEM), energy dispersive spectrometer (EDS), thermogravimetry/differential scanning calorimetry (TG/DCS), and temperature-programmed reduction (TPR) were used to characterize the structure and morphology properties of the synthesized composites. The catalytic ability test of 1,2-dichlorobenzene (o-DCB) over the catalysts was conducted in a fixed-bed flow reactor with a gas hourly space velocity (GHSV) of 30,000 h-1 to investigate the catalytic performance of the prepared composites. The results indicated that the combined Cr2O3 and Mn2O3 phases supported on cordierite possessed a special ball-shaped and better redox property in the catalyst prepared by the Co-precipitation method with a Cr/Mn atomic ratio of 2∶5, which was conducive to the increase of the synergistic effect and subsequently enhancement of the catalytic performance. Furthermore, it exhibited better stability within 60 h, which indicates a good prospect for industrial applications.

Rodent models of transcranial magnetic stimulation (TMS) play a crucial role in aiding the understanding of the cellular and molecular mechanisms underlying TMS induced plasticity. Rodent-specific TMS have previously been used to deliver focal stimulation at the cost of stimulus intensity (12 mT). Here we describe two novel TMS coils designed to deliver repetitive TMS (rTMS) at greater stimulation intensities whilst maintaining spatial resolution. Two circular coils (8 mm outer diameter) were constructed with either an air or pure iron-core. Peak magnetic field strength for the air and iron-cores were 90 and 120 mT, respectively, with the iron-core coil exhibiting less focality. Coil temperature and magnetic field stability for the two coils undergoing rTMS, were similar at 1 Hz but varied at 10 Hz. Finite element modeling of 10 Hz rTMS with the iron-core in a simplified rat brain model suggests a peak electric field of 85 and 12.7 V/m, within the skull and the brain, respectively. Delivering 10 Hz rTMS to the motor cortex of anaesthetized rats with the iron-core coil significantly increased motor evoked potential amplitudes immediately after stimulation (n = 4). Our results suggest these novel coils generate modest magnetic and electric fields, capable of altering cortical excitability and provide an alternative method to investigate the mechanisms underlying rTMS-induced plasticity in an experimental setting.

Low intensity repetitive Transcranial Magnetic Stimulation (LI-rTMS), a non-invasive form of brain stimulation, has been shown to induce structural and functional brain plasticity, including short distance axonal sprouting. However, the potential for LI-rTMS to promote axonal regeneration following neurotrauma has not been investigated. This study examined the effect of LI-rTMS on retinal ganglion cell (RGC) survival, axon regeneration and levels of BDNF in an optic nerve crush neurotrauma model. Adult C57Bl/6J mice received a unilateral intraorbital optic nerve crush. Mice received 10 minutes of sham (handling control without stimulation) (n=6) or LI-rTMS (n = 8) daily stimulation for 14 days to the operated eye. Immunohistochemistry was used to assess RGC survival (β-3 Tubulin) and axon regeneration across the injury (GAP43). Additionally, BDNF expression was quantified in a separate cohort by ELISA in the retina and optic nerve of injured (optic nerve crush) (sham n = 5, LI-rTMS n = 5) and non-injured mice (sham n = 5, LI-rTMS n = 5) that received daily stimulation as above for 7 days. Following 14 days of LI-rTMS there was no significant difference in mean RGC survival between sham and treated animals (p>0.05). Also, neither sham nor LI-rTMS animals showed GAP43 positive labelling in the optic nerve, indicating that regeneration did not occur. At 1 week, there was no significant difference in BDNF levels in the retina or optic nerves between sham and LI-rTMS in injured or non-injured mice (p>0.05). Although LI-rTMS has been shown to induce structural and molecular plasticity in the visual system and cerebellum, our results suggest LI-rTMS does not induce neuroprotection or regeneration following a complete optic nerve crush. These results help define the therapeutic capacity and limitations of LI-rTMS in the treatment of neurotrauma.