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Post-stroke fatigue is a chronic problem with significant impact on morbidity and mortality, which urgently needs effective treatments. The last decade has seen a considerable increase in interest in understanding the pathophysiology of fatigue and developing treatments. In this review, following a summary of theoretical frameworks to understand chronic fatigue, I make a case for why phenotyping fatigue is a necessary step to fully understand pathophysiology, which in turn is essential for the development of robust treatments. I then appraise current post-stroke fatigue literature with the view of identifying post-stroke fatigue phenotypes., (© 2024 The Author(s). The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Neurons in the CNS lose regenerative potential with maturity, leading to minimal corticospinal tract (CST) axon regrowth after spinal cord injury (SCI). In young rodents, knockdown of PTEN, which antagonizes PI3K signaling by hydrolyzing PIP3, promotes axon regeneration following SCI. However, this effect diminishes in adults, potentially due to lower PI3K activation leading to reduced PIP3. This study explores whether increased PIP3 generation can promote long-distance regeneration in adults. We used a hyperactive PI3K, PI3Kδ (PIK3CD), to boost PIP3 levels in mature cortical neurons and assessed CST regeneration after SCI. Adult rats received AAV1-PIK3CD and AAV1-eGFP, or AAV1-eGFP alone, in the sensorimotor cortex concurrent with a C4 dorsal SCI. Transduced neurons showed increased pS6 levels, indicating elevated PI3K/Akt/mTOR signaling. CST regeneration, confirmed with retrograde tracing, was evaluated up to 16 weeks post injury. At 12 weeks, ∼100 axons were present at lesion sites, doubling to 200 by 16 weeks, with regeneration indices of 0.1 and 0.2, respectively. Behavioral tests showed significant improvements in paw reaching, grip strength, and ladder-rung walking in PIK3CD-treated rats, corroborated by electrophysiological recordings of cord dorsum potentials and distal flexor muscle electromyography. Thus, PI3Kδ upregulation in adult cortical neurons enhances axonal regeneration and functional recovery post SCI., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Knee joint disorders pose a significant and growing challenge to global healthcare systems. Recent advancements in robotics, sensing technologies, and artificial intelligence have driven the development of robot-assisted therapies, reducing the physical burden on therapists and improving rehabilitation outcomes. This study presents a novel knee exoskeleton designed for safe and adaptive rehabilitation, specifically targeting bed-bound stroke patients to enable early intervention. The exoskeleton comprises a leg splint, thigh splint, and an actuator, incorporating a series elastic actuator (SEA) to enhance torque density and provide intrinsic compliance. A variable impedance control method was also implemented to achieve accurate position tracking of the exoskeleton, and performance tests were conducted with and without human participants. A preliminary clinical study involving two stroke patients demonstrated the exoskeleton's potential in reducing muscle spasticity, particularly at faster movement velocities. The key contributions of this study include the design of a compact SEA with improved torque density, the development of a knee exoskeleton equipped with a cascaded position controller, and a clinical test validating its effectiveness in alleviating spasticity in stroke patients. This study represents a significant step forward in the application of SEA for robot-assisted rehabilitation, offering a promising approach to the treatment of knee joint disorders.

Current clinical assessment tools don't fully capture the genuine neural deficits experienced by chronic stroke survivors and, consequently, they don't fully explain motor function throughout everyday life. Towards addressing this problem, here we aimed to characterise post-stroke alterations in upper-limb control from a novel perspective to the muscle synergy by applying, for the first time, a computational approach that quantifies diverse types of functional muscle interactions (i.e. functionally-similar (redundant), -complementary (synergistic) and -independent (unique)). From single-trials of a simple forward pointing movement, we extracted networks of functionally diverse muscle interactions from chronic stroke survivors and unimpaired controls, identifying shared and group-specific modules across each interaction type (i.e. redundant, synergistic and unique). Reconciling previous studies, we found evidence for both the concurrent preservation of healthy functional modules post-stroke and muscle network structure alterations underpinned by systemic muscle interaction re-weighting and functional reorganisation across all interaction types. Cluster analysis of stroke survivors revealed two distinct patient subgroups from each interaction type that all distinguished less impaired individuals who were able to adopt novel motor patterns different to unimpaired controls from more severely impaired individuals who did not. Our work here provides a nuanced account of post-stroke functional impairment and, in doing so, paves new avenues towards progressing the clinical use case of muscle synergy analysis., Competing Interests: Declarations. Conflict of interest: The authors declare no conflicts of interest were present., (© 2024. The Author(s).)

Neuropathic pain following peripheral nerve injury results from maladaptive changes in neurons and immune cells contribution to mechanisms underlying chronic pain. Specifically, in dorsal root ganglia (DRG), sensory neuron cell bodies release extracellular vesicles (EVs) which promote pro-inflammatory macrophage accumulation that facilitates nociceptive signalling. Here, we show that macrophages shuttle EVs to neurons. Indeed, bone marrow-derived macrophages (BMDMs) release EVs containing microRNA-155 (miR-155) which are taken up by cultured sensory neurons. EV-mediated transfer of miR-155 suppresses phosphatase Ship1 expression and increases cytokine interleukin-6 (IL-6) contents. Intrathecal-injected BMDM-derived EVs accumulate in lumbar DRG and EVs containing miR-155 antagomir result in Ship1 upregulation, Il6 downregulation in neurons in concomitance to attenuation of neuropathic mechanical hypersensitivity. These data suggest that, under neuropathic conditions, pro-inflammatory macrophages shuttle EV-containing miR-155 to neurons and contribute to the expression of pronociceptive IL-6 in DRG., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

The muscle synergy concept suggests that the human motor system is organized into functional modules composed of muscles " working together " toward common task goals. This study offers a nuanced computational perspective to muscle synergies, where muscles interacting across multiple scales have functionally similar, complementary, and independent roles. Making this viewpoint implicit to a methodological approach applying Partial Information Decomposition to large-scale muscle activations, we unveiled nested networks of functionally diverse inter- and intramuscular interactions with distinct functional consequences on task performance. The effectiveness of this approach is demonstrated using simulations and by extracting generalizable muscle networks from benchmark datasets of muscle activity. Specific network components are shown to correlate with (1) balance performance and (2) differences in motor variability between young and older adults. By aligning muscle synergy analysis with leading theoretical insights on movement modularity, the mechanistic insights presented here suggest the proposed methodology offers enhanced research opportunities toward health and engineering applications., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Myosin 5a (Myo5a) is a dimeric processive motor protein that transports cellular cargos along filamentous actin (F-actin). Its long lever is responsible for its large power-stroke, step size, and load-bearing ability. Little is known about the levers' structure and physical properties, and how they contribute to walking mechanics. Using cryoelectron microscopy (cryo-EM) and molecular dynamics (MD) simulations, we resolved the structure of monomeric Myo5a, comprising the motor domain and full-length lever, bound to F-actin. The range of its lever conformations revealed its physical properties, how stiffness varies along its length and predicts a large, 35 nm, working stroke. Thus, the newly released trail head in a dimeric Myo5a would only need to perform a small diffusive search for its new binding site on F-actin, and stress would only be generated across the dimer once phosphate is released from the lead head, revealing new insight into the walking behavior of Myo5a., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Elective and emergency Caesarean section (C-section) procedures are on the rise, exceeding the recommended guidelines by the World Health Organization. Higher morbidities and long-term health conditions are correlated to C-section deliveries, including neurodevelopmental disorders. During C-section delivery, newborns are not exposed to the vaginal commensal flora, which impedes the early establishment of the gut microbiota. The latter is essential for adequate neuro-immune processes to take place during infancy. In this study, we used a validated model of mice born by C-section (CSD), which mimics clinical observations of dysregulated gut microbiota. Animals were either born naturally or by CSD, before being adopted by dams who underwent delivery within the 12 preceding hours. Behavioural analyses were conducted at post-natal day (PND) 21 and 55. Our results indicate that animals born by C-section present significantly higher body weight in late (PND40-P53) but not early adolescence (PND21-P27), compared to animals born by vaginal delivery (VD). Male animals delivered by C-section presented significantly lower exploration time of the novel arm in the Y Maze test at PND55. However, at PND21, abnormal social interaction was witnessed in male and female animals born by CSD, with significantly decreased time spent interacting during the social interaction test. At both PND21 and PND55, animals from both sexes born by C-section presented significantly decreased time spent in the open arm of the Elevated Plus Maze test, compared to control animals. We then measured the expression of genes associated to neuroimmune interactions (microglia phenotype), inflammatory mediators and lipids in several brain structures of VD and CSD mice at PND21 and PND55. At weaning, animals born by CSD presented altered microglia, inflammatory and lipid metabolism signatures, with increased expression of Cd36, Csf1r and Tnfα in different brain regions of males, but not in females. At PND64, Csf1r, Tmem119 as well as C3ar1 were significantly increased in males born by C-section, but not in females. In males born by vaginal delivery, the expression of Cd36 at PND64 was correlated to anxiety at PND55, whilst a correlation between the expression of Clec7a and the number of head dippings in the elevated plus maze was also noted in males born by CSD. Altogether, our study shows altered emotional behaviour in animals delivered by CSD, which is likely explained by underlying neuro-inflammatory processes in different brain regions. Our work further supports the long-term consequences of CSD on brain health., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethics approval: All experiments were conducted in accordance with the criteria outlined in the European Communities Council Directive 2010/63/EU for animal experiments. Ethical approvals were obtained from the national ethical committee for the care and use of animals (Approval numbers: APAFIS 2018061514419181 #15533 and APAFIS 202001072155893 #23506)., (© 2024. The Author(s).)

Cell-to-cell communication is a major process for accommodating cell functioning to changes in the environments and to preserve tissue and organism homeostasis. It is achieved by different mechanisms characterized by the origin of the message, the molecular nature of the messenger, its speed of action and its reach. Purinergic signalling is a powerful mechanism initiated by extracellular nucleotides, such as ATP, acting on plasma membrane purinoreceptors. Purinergic signalling is tightly controlled in time and space by the action of ectonucleotidases. Recent studies have highlighted the critical role of purinergic signalling in controlling the generation, release and fate of extracellular vesicles and, in this way, mediating long-distance responses. Most of these discoveries have been made in immune and cancer cells. This review is aimed at establishing the current knowledge on the way which purinoreceptors control extracellular vesicle-mediated communications and consequences for recipient cells., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Escape jet propulsion swimming in cuttlefish (Sepia officinalis) is powered by the circular muscles surrounding the mantle cavity. This mode of locomotion is energetically costly compared with undulatory swimming. The energetic cost of swimming is determined by the mechanical power requirements and the efficiency with which chemical energy is transferred into useful mechanical work. One step in this energy transduction process is the transfer of energy from ATP hydrolysis into mechanical work by the muscles. Here, we determined the efficiency of this step, termed the contractile efficiency. Muscle preparations from the circular muscles of the mantle cavity were subjected to sinusoidal length changes at different cycle frequencies, and stimulated with a phase and duration that maximised initial net work. Changes in ATP, arginine phosphate and octopine content between control and exercised muscles were determined and used to calculate the energy released from ATP hydrolysis (Emet). The maximum contractile efficiency (the ratio of net work to Emet) was 0.37, occurring at the same cycle frequency at which mechanical power was maximal and that was used during jet propulsion swimming, suggesting that cuttlefish muscle is adapted to generate muscular power efficiently. The overall efficiency of cuttlefish jet propulsion swimming was estimated to be 0.17, which is broadly comparable to that measured during animal flight and human-powered pedalled locomotion, indicating the high energetic costs of jet propulsion swimming are not due to inefficient locomotion per se; instead, they result from the relatively high mechanical power requirements., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

The work loop technique was developed to assess muscle performance during cyclical length changes with phasic activation, simulating the in vivo conditions of many muscles, particularly during locomotion. To estimate muscle function in vivo, the standard approach involves subjecting a muscle to length trajectories and activation timings derived from in vivo measurements, whilst simultaneously measuring force. However, the stimulation paradigm typically used, supramaximal, 'square-wave' stimulation, does not accurately reflect the graded intensity of activation observed in vivo. While the importance of the timing and duration of stimulation within the cycle on estimates of muscle performance has long been established, the importance of graded muscle activation has not been investigated. In this study, we investigated how the activation pattern affects muscle performance by comparing square-wave, supramaximal activation with a graded in vivo activation pattern. First, we used in vivo electromyography-derived activation patterns and fibre strains from the rabbit digastric muscle during mastication and replayed them in situ. Second, we used Hill-type musculoskeletal model-derived activation patterns and fibre strains in a trotting mouse, replayed ex vivo in the soleus (SOL) and extensor digitorum longus (EDL) muscles. In the rabbit digastric muscle, square-wave activation led to an 8-fold higher estimate of net power, compared with the in vivo graded activation pattern. Similarly, in the mouse SOL and EDL, supramaximal, square-wave activation resulted in significantly greater positive and negative muscle work. These findings highlight that realistic interpretations of in vivo muscle function rely upon more accurate representations of muscle activation intensity., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Objectives: To assess the feasibility, acceptability, and preliminary effectiveness of implementing a home-based aerobic and resistance exercise for patients with breast cancer receiving endocrine treatment in Indonesia., Methods: This is a mixed methods study with concurrent design consisting of quantitative single-arm pre-post intervention and qualitative study. We recruited patients with breast cancer ( N  = 36) receiving endocrine treatment and assigned 12 weeks of home-based pedometer-driven walking and resistance exercises using therapeutic bands. Descriptive statistics were used to assess the feasibility (recruitment, retention, and adherence) and safety. The modified Bruce treadmill test was used to measure predicted aerobic capacity (V̇O 2 peak). Quality of life and fatigue were assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire and fatigue severity scale. Measurements were performed at baseline and post-intervention and analyzed with the paired t -test or Wilcoxon test. Semi-structured interviews and thematic analysis were conducted post-intervention to explore patients' acceptability., Results: The results showed a recruitment rate of 75%, retention rate of 89%, and adherence rates were 53% for aerobic and 78% for resistance exercise. No severe adverse events were reported. Post-intervention interviews identified positive attitudes toward the intervention, with low burden and high perceived benefit. Exercise duration and predicted V̇O 2  peak increased significantly (+1.1 min, p  = 0.001 and +2.3 ml/kg/min, p  = 0.043), but no significant change was detected for Quality of Life ( p  > 0.050) or fatigue severity ( p  = 0.299)., Conclusions: A home-based aerobic and resistance exercise was feasible when implemented in the context of routine care in our study population, improving predicted aerobic capacity. Further research is required to understand limited changes to Quality of Life and fatigue and adaptations to support implementation in additional sites in Indonesia., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2024.)

Large-scale genome-wide association studies (GWASs) have associated intronic variants in PDE4B , encoding cAMP-specific phosphodiesterase-4B (PDE4B), with increased risk for post-traumatic stress disorder (PTSD), as well as schizophrenia and substance use disorders that are often comorbid with it. However, the pathophysiological mechanisms of genetic risk involving PDE4B are poorly understood. To examine the effects of PDE4B variation on phenotypes with translational relevance to psychiatric disorders, we focused on PDE4B missense variant M220T, which is present in the human genome as rare coding variant rs775201287. When expressed in HEK-293 cells, PDE4B1-M220T exhibited an attenuated response to a forskolin-elicited increase in the intracellular cAMP concentration. In behavioral tests, homozygous Pde4b male mice with a C57BL/6JJcl background exhibited increased reactivity to novel environments, startle hyperreactivity, prepulse inhibition deficits, altered cued fear conditioning, and enhanced spatial memory, accompanied by an increase in cAMP signaling pathway-regulated expression of BDNF in the hippocampus. In response to a traumatic event (10 tone-shock pairings), neuronal activity was decreased in the cortex but enhanced in the amygdala and hippocampus of M220T male mice with a C57BL/6JJcl background exhibited increased reactivity to novel environments, startle hyperreactivity, prepulse inhibition deficits, altered cued fear conditioning, and enhanced spatial memory, accompanied by an increase in cAMP signaling pathway-regulated expression of BDNF in the hippocampus. In response to a traumatic event (10 tone-shock pairings), neuronal activity was decreased in the cortex but enhanced in the amygdala and hippocampus of Pde4b M220T mice also exhibited a slower decay in freezing at 15 and 30 d post-trauma, demonstrating enhanced persistence of traumatic memories, similar to that exhibited by PTSD patients. These findings provide substantive mouse model evidence linking PDE4B variation to PTSD-relevant phenotypes and thus highlight how genetic variation of PDE4B may contribute to PTSD risk.Pde4b M220T mice exhibited increased startle hyperreactivity and decreased plasma corticosterone levels, similar to phenotypes exhibited by PTSD patients. Trauma-exposed Pde4b M220T mice also exhibited a slower decay in freezing at 15 and 30 d post-trauma, demonstrating enhanced persistence of traumatic memories, similar to that exhibited by PTSD patients. These findings provide substantive mouse model evidence linking PDE4B variation to PTSD-relevant phenotypes and thus highlight how genetic variation of PDE4B may contribute to PTSD risk., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Lipina et al.)

Background: The COVID-19 outbreak meant that people were unable to attend art-based community classes such as dance. In response, activities transitioned to digital modes of delivery. In this study, we aimed to explore the feasibility, inclusivity, and impact of transitioning to an online dance class., Methods: Thirty community-dwelling older adults (59-84 years old) were recruited from community groups in Yorkshire (UK). Participants completed an online survey at baseline and after attending 8 weeks of online dance classes. The survey captured perceived benefits on physical activity and mental wellbeing. Two separate focus groups ( N  = 12) were conducted to explore if the online dance transition could be an opportunity to keep this group active and socially connected., Results: Survey data revealed no significant difference in the amount of time engaged in physical activity, but mental wellbeing significantly improved. Themes from the focus groups included holistic wellbeing related to the experience of dance, inclusive participation of online dance, and online dance facilitating social connection and sense of belonging., Conclusions: The research provided insight into the online transition of a dance class for older adults, especially regarding inclusivity, sense of belonging and social connection.

Muscle spindle abundance is highly variable in vertebrates, but the functional determinants of this variation are unclear. Recent work has shown that human leg muscles with the lowest abundance of muscle spindles primarily function to lengthen and absorb energy, while muscles with a greater spindle abundance perform active-stretch-shorten cycles with no net work, suggesting that muscle spindle abundance may be underpinned by muscle function. Compared with other mammalian muscles, the digastric muscle contains the lowest abundance of muscle spindles and, therefore, might be expected to generate substantial negative work. However, it is widely hypothesised that as a jaw-opener (anatomically) the digastric muscle would primarily function to depress the jaw, and consequently do positive work. Through a combination of X-ray reconstruction of moving morphology (XROMM), electromyography and fluoromicrometry, we characterised the 3D kinematics of the jaw and digastric muscle during feeding in rabbits. Subsequently, the work loop technique was used to simulate in vivo muscle behaviour in situ, enabling muscle force to be quantified in relation to muscle strain and hence determine the muscle's function during mastication. When functioning on either the working or balancing side, the digastric muscle generates a large amount of positive work during jaw opening, and a large amount of negative work during jaw closing, on average producing a relatively small amount of net negative work. Our data therefore further support the hypothesis that muscle spindle abundance is linked to muscle function; specifically, muscles that absorb a relatively large amount of negative work have a low spindle abundance., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Neuromyelitis optica (NMO) arises from primary astrocytopathy induced by autoantibodies targeting the astroglial protein aquaporin 4 (AQP4), leading to severe neurological sequelae such as vision loss, motor deficits, and cognitive decline. Mounting evidence has shown that dysregulated activation of complement components contributes to NMO pathogenesis. Complement C3 deficiency has been shown to protect against hippocampal neurodegeneration and cognitive decline in neurodegenerative disorders (e.g., Alzheimer's disease, AD) and autoimmune diseases (e.g., multiple sclerosis, MS). However, whether inhibiting the C3 signaling can ameliorate cognitive dysfunctions in NMO remains unclear. In this study, we found that the levels of C3a, a split product of C3, significantly correlate with cognitive impairment in our patient cohort. In response to the stimulation of AQP4 autoantibodies, astrocytes were activated to secrete complement C3, which inhibited the development of cultured neuronal dendritic arborization. NMO mouse models exhibited reduced adult hippocampal newborn neuronal dendritic and spine development, as well as impaired learning and memory functions, which could be rescued by decreasing C3 levels in astrocytes. Mechanistically, we found that C3a engaged with C3aR to impair neuronal development by dampening β-catenin signalling. Additionally, inhibition of the C3-C3aR-GSK3β/β-catenin cascade restored neuronal development and ameliorated cognitive impairments. Collectively, our results suggest a pivotal role of the activation of the C3-C3aR network in neuronal development and cognition through mediating astrocyte and adult-born neuron communication, which represents a potential therapeutic target for autoimmune-related cognitive impairment diseases., Competing Interests: Declaration of Competing Interest The authors declare no competing interestsm., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Meta-analysis of genome-wide association study data has implicated PDE4B in the pathogenesis of Alzheimer's disease (AD), the leading cause of senile dementia. PDE4B encodes one of four subtypes of cyclic adenosine monophosphate (cAMP)-specific phosphodiesterase-4 (PDE4A-D). To interrogate the involvement of PDE4B in the manifestation of AD-related phenotypes, the effects of a hypomorphic mutation (Pde4b Y358C ) that decreases PDE4B's cAMP hydrolytic activity were evaluated in the App NL-G-F knock-in mouse model of AD using the Barnes maze test of spatial memory, 14 C-2-deoxyglucose autoradiography, thioflavin-S staining of β-amyloid (Aβ) plaques, and inflammatory marker assay and transcriptomic analysis (RNA sequencing) of cerebral cortical tissue. At 12 months of age, App NL-G-F mice exhibited spatial memory and brain metabolism deficits, which were prevented by the hypomorphic PDE4B in App NL-G-F /Pde4b Y358C mice, without a decrease in Aβ plaque burden. RNA sequencing revealed that, among the 531 transcripts differentially expressed in App NL-G-F versus wild-type mice, only 13 transcripts from four genes - Ide, Btaf1, Padi2, and C1qb - were differentially expressed in App NL-G-F /Pde4b Y358C versus App NL-G-F mice, identifying their potential involvement in the protective effect of hypomorphic PDE4B. Our data demonstrate that spatial memory and cerebral glucose metabolism deficits exhibited by 12-month-old App NL-G-F mice are prevented by targeted inhibition of PDE4B. To our knowledge, this is the first demonstration of a protective effect of PDE4B subtype-specific inhibition in a preclinical model of AD. It thus identifies PDE4B as a key regulator of disease manifestation in the App NL-G-F model and a promising therapeutic target for AD., (© 2024. The Author(s).)

G protein-coupled receptors (GPCRs) are the largest group of membrane receptors in the central nervous system and one of the key proteins for signal transduction between cells. Currently, many drugs available on the market act via GPCRs and these receptors remain attractive targets for the treatment of brain disorders, including alcohol use disorder (AUD). Here, we describe the most recent literature, with a primary focus on the past 5 years, on GPCR targets with the potential for reducing behaviours associated with excessive alcohol intake. Specifically, we focus on preclinical evidence of compounds with attractive pharmacological profiles and potential for future clinical investigation for the treatment of AUD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Structural neuroplasticity such as neurite extension and dendritic spine dynamics is enhanced by brain-derived neurotrophic factor (BDNF) and impaired by types of inhibitory molecules that induce growth cone collapse and actin depolymerization, for example, myelin-associated inhibitors, chondroitin sulfate proteoglycans, and negative guidance molecules. These inhibitory molecules can activate RhoA/rho-associated coiled-coil containing protein kinase (ROCK) signaling (known to restrict structural plasticity). Intermittent hypoxia (IH) and high-intensity interval training (HIIT) are known to upregulate BDNF that is associated with improvements in learning and memory and greater functional recovery following neural insults. We investigated whether the RhoA/ROCK signaling pathway is also modulated by IH and HIIT in the hippocampus, cortex, and lumbar spinal cord of male Wistar rats. The gene expression of 25 RhoA/ROCK signaling pathway components was determined following IH, HIIT, or IH combined with HIIT (30 min/day, 5 days/wk, 6 wk). IH included 10 3-min bouts that alternated between hypoxia (15% O 2 ) and normoxia. HIIT included 10 3-min bouts alternating between treadmill speeds of 50 cm·s -1 and 15 cm·s -1 . In the hippocampus, IH and HIIT significantly downregulated Acan and NgR2 mRNA that are involved in the inhibition of neuroplasticity. However, IH and IH + HIIT significantly upregulated Lingo-1 and NgR3 in the cortex. This is the first time IH and HIIT have been linked to the modulation of plasticity-inhibiting pathways. These results provide a fundamental step toward elucidating the interplay between the neurotrophic and inhibitory mechanisms involved in experience-driven neural plasticity that will aid in optimizing physiological interventions for the treatment of cognitive decline or neurorehabilitation. NEW & NOTEWORTHY Intermittent hypoxia (IH) and high-intensity interval training (HIIT) enhance neuroplasticity and upregulate neurotrophic factors in the central nervous system (CNS). We provide evidence that IH and IH + HIIT also have the capacity to regulate genes involved in the RhoA/ROCK signaling pathway that is known to restrict structural plasticity in the CNS. This provides a new mechanistic insight into how these interventions may enhance hippocampal-related plasticity and facilitate learning, memory, and neuroregeneration.

Introduction: The accuracy of musculoskeletal models and simulations as methods for predicting muscle functional outputs is always improving. However, even the most complex models contain various assumptions and simplifications in how muscle force generation is simulated. One common example is the application of a generalised ("generic") force-velocity relationship, derived from a limited data set to each muscle within a model, uniformly across all muscles irrespective of whether those muscles have "fast" or "slow" contractile properties. Methods: Using a previously built and validated musculoskeletal model and simulation of trotting in the mouse hindlimb, this work examines the predicted functional impact of applying muscle-specific force-velocity properties to typically fast (extensor digitorum longus; EDL) and slow-contracting (soleus; SOL) muscles. Results: Using "real" data led to EDL producing more positive work and acting significantly more spring-like, and soleus producing more negative work and acting more brake-like in function compared to muscles modelled using "generic" force-velocity data. Extrapolating these force-velocity properties to other muscles considered "fast" or "slow" also substantially impacted their predicted function. Importantly, this also further impacted EDL and SOL function beyond that seen when changing only their properties alone, to a point where they show an improved match to ex vivo experimental data. Discussion: These data suggest that further improvements to how musculoskeletal models and simulations predict muscle function should include the use of different values defining their force-velocity relationship depending on their fibre-type composition., 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., (Copyright © 2024 Charles, Kissane and Askew.)

Background: Parkinson's disease (PD) is the second most common neurodegenerative disease, following Alzheimer's. It is characterized by the aggregation of α-synuclein into Lewy bodies and Lewy neurites in the brain. Microglia-driven neuroinflammation may contribute to neuronal death in PD; however, the exact role of microglia remains unclear and has been understudied. The A53T mutation in the gene coding for α-synuclein has been linked to early-onset PD, and exposure to A53T mutant human α-synuclein increases the potential for inflammation of murine microglia. To date, its effect has not been studied in human microglia., Methods: Here, we used 2-dimensional cultures of human pluripotent stem cell-derived microglia and transplantation of these cells into the mouse brain to assess the cell autonomous effects of the A53T mutation on human microglia., Results: We found that A53T mutant human microglia had an intrinsically increased propensity toward proinflammatory activation upon inflammatory stimulus. Additionally, transplanted A53T mutant microglia showed a strong decrease in catalase expression in noninflammatory conditions and increased oxidative stress., Conclusions: Our results indicate that A53T mutant human microglia display cell autonomous phenotypes that may worsen neuronal damage in early-onset PD., (Crown Copyright © 2024. Published by Elsevier Inc. All rights reserved.)

The Na + -activated K + channel K Na 1.1, encoded by the KCNT1 gene, is an important regulator of neuronal excitability. How intracellular Na + ions bind and increase channel activity is not well understood. Analysis of K Na 1.1 channel structures indicate that there is a large twisting of the βN-αQ loop in the intracellular RCK2 domain between the inactive and Na + -activated conformations, with a lysine (K885, human subunit numbering) close enough to potentially form a salt bridge with an aspartate (D839) in βL in the Na + -activated state. Concurrently, an aspartate (D884) adjacent in the same loop adopts a position within a pocket formed by the βO strand. In carrying out mutagenesis and electrophysiology with human K Na 1.1, we found that alanine substitution of selected residues in these regions resulted in almost negligible currents in the presence of up to 40 mM intracellular Na + . The exception was D884A, which resulted in constitutively active channels in both the presence and absence of intracellular Na + . Further mutagenesis of this site revealed an amino acid size-dependent effect. Substitutions at this site by an amino acid smaller than aspartate (D884V) also yielded constitutively active K Na 1.1, and D884I had Na + dependence similar to wild-type K Na 1.1, while increasing the side-chain size larger than aspartate (D884E or D884F) yielded channels that could not be activated by up to 40 mM intracellular Na + . We conclude that Na + binding results in a conformational change that accommodates D884 in the βO pocket, which triggers further conformational changes in the RCK domains and channel activation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Biophysical Society. Published by Elsevier Inc. All rights reserved.)

Background: Oxidative stress is a well-known pathological factor driving neuronal loss and age-related neurodegenerative diseases. Melatonin, coenzyme Q10 and lecithin are three common nutrients with an antioxidative capacity. Here, we examined the effectiveness of them administrated individually and in combination in protecting against oxidative stress-induced neuronal death in vitro, and neurodegenerative conditions such as Alzheimer's disease and associated deficits in vivo., Methods: Mouse neuroblastoma Neuro-2a (N2a) cells were exposed with H 2 O 2 for 6 h, and subsequently treated with melatonin, coenzyme Q10, and lecithin alone or in combination for further 24 h. Cell viability was assessed using the CCK-8 assay. Eight-week-old male mice were intraperitoneally injected with D-(+)-galactose for 10 weeks and administrated with melatonin, coenzyme Q10, lecithin, or in combination for 5 weeks starting from the sixth week, followed by behavioral tests to assess the effectiveness in mitigating neurological deficits, and biochemical assays to explore the underlying mechanisms., Results: Exposure to H 2 O 2 significantly reduced the viability of N2a cells and increased oxidative stress and tau phosphorylation, all of which were alleviated by treatment with melatonin, coenzyme Q10, lecithin alone, and, most noticeably, by combined treatment. Administration of mice with D-(+)-galactose-induced oxidative stress and tau phosphorylation, brain aging, impairments in learning and memory, anxiety- and depression-like behaviors, and such detrimental effects were mitigated by melatonin, coenzyme Q10, lecithin alone, and, most consistently, by combined treatment., Conclusions: These results suggest that targeting oxidative stress via supplementation of antioxidant nutrients, particularly in combination, is a better strategy to alleviate oxidative stress-mediated neuronal loss and brain dysfunction due to age-related neurodegenerative conditions., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Human epidermal growth factor receptors (EGFR), namely ErbB1/HER1, ErbB2/HER2/neu, ErbB3/HER3, and ErbB4/HER4, the trans-membrane family of tyrosine kinase receptors, are overexpressed in many types of cancers. These receptors play an important role in cell proliferation, differentiation, invasion, metastasis and angiogenesis including unregulated activation of cancer cells. Overexpression of ErbB1 and ErbB2 that occurs in several types of cancers is associated with poor prognosis leading to resistance to ErbB1-directed therapies. In this connection, promising strategy to overcome the disadvantages of the existing chemotherapeutic drugs is the use of short peptides as anticancer agents. In the present study, we have performed virtual high throughput screening of natural peptides against ErbB1 and ErbB2 to identify potential dual inhibitors and identified five inhibitors based on their binding affinities, ADMET analysis, MD simulation studies and calculation of free energy of binding. These natural peptides could be further exploited for developing drugs for treating cancer.Communicated by Ramaswamy H. Sarma.

Older adults (OAs) are typically slower and/or less accurate in forming perceptual choices relative to younger adults. Despite perceptual deficits, OAs gain from integrating information across senses, yielding multisensory benefits. However, the cognitive processes underlying these seemingly discrepant ageing effects remain unclear. To address this knowledge gap, 212 participants (18-90 years old) performed an online object categorisation paradigm, whereby age-related differences in Reaction Times (RTs) and choice accuracy between audiovisual (AV), visual (V), and auditory (A) conditions could be assessed. Whereas OAs were slower and less accurate across sensory conditions, they exhibited greater RT decreases between AV and V conditions, showing a larger multisensory benefit towards decisional speed. Hierarchical Drift Diffusion Modelling (HDDM) was fitted to participants' behaviour to probe age-related impacts on the latent multisensory decision formation processes. For OAs, HDDM demonstrated slower evidence accumulation rates across sensory conditions coupled with increased response caution for AV trials of higher difficulty. Notably, for trials of lower difficulty we found multisensory benefits in evidence accumulation that increased with age, but not for trials of higher difficulty, in which increased response caution was instead evident. Together, our findings reconcile age-related impacts on multisensory decision-making, indicating greater multisensory evidence accumulation benefits with age underlying enhanced decisional speed., (© 2024. The Author(s).)

We report that diazepam binding inhibitor (DBI) is a glial messenger mediating crosstalk between satellite glial cells (SGCs) and sensory neurons in the dorsal root ganglion (DRG). DBI is highly expressed in SGCs of mice, rats, and humans, but not in sensory neurons or most other DRG-resident cells. Knockdown of DBI results in a robust mechanical hypersensitivity without major effects on other sensory modalities. In vivo overexpression of DBI in SGCs reduces sensitivity to mechanical stimulation and alleviates mechanical allodynia in neuropathic and inflammatory pain models. We further show that DBI acts as an unconventional agonist and positive allosteric modulator at the neuronal GABAA receptors, particularly strongly affecting those with a high-affinity benzodiazepine binding site. Such receptors are selectively expressed by a subpopulation of mechanosensitive DRG neurons, and these are also more enwrapped with DBI-expressing glia, as compared with other DRG neurons, suggesting a mechanism for a specific effect of DBI on mechanosensation. These findings identified a communication mechanism between peripheral neurons and SGCs. This communication modulates pain signaling and can be targeted therapeutically.

Do motor patterns of object lifting movements change as a result of ageing? Here we propose a methodology for the characterization of these motor patterns across individuals of different age groups. Specifically, we employ a bimanual grasp-lift-replace protocol with younger and older adults and combine measurements of muscle activity with grip and load forces to provide a window into the motor strategies supporting effective object lifts. We introduce a tensor decomposition to identify patterns of muscle activity and grip-load force ratios while also characterizing their temporal profiles and relative activation across object weights and participants of different age groups. We then probe age-induced changes in these components. A classification analysis reveals three motor components that are differentially recruited between the two age groups. Linear regression analyses further show that advanced age and poorer manual dexterity can be predicted by the coupled activation of forearm and hand muscles which is associated with high levels of grip force. Our findings suggest that ageing may induce stronger muscle couplings in distal aspects of the upper limbs, and a less economic grasping strategy to overcome age-related decline in manual dexterity., (© 2024. The Author(s).)

Membrane forces shift the equilibria of mechanosensitive channels enabling them to convert mechanical cues into electrical signals. Molecular tools to stabilize and methods to capture their highly dynamic states are lacking. Cyclodextrins can mimic tension through the sequestering of lipids from membranes. Here we probe the conformational ensemble of MscS by EPR spectroscopy, the lipid environment with NMR, and function with electrophysiology under cyclodextrin-induced tension. We show the extent of MscS activation depends on the cyclodextrin-to-lipid ratio, and that lipids are depleted slower when MscS is present. This has implications in MscS' activation kinetics when distinct membrane scaffolds such as nanodiscs or liposomes are used. We find MscS transits from closed to sub-conducting state(s) before it desensitizes, due to the lack of lipid availability in its vicinity required for closure. Our approach allows for monitoring tension-sensitive states in membrane proteins and screening molecules capable of inducing molecular tension in bilayers., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Despite physical activity (PA) providing specific health benefits during pregnancy and the postpartum period, many women report decreased PA during this time. Provision of PA advice has been found to be lacking amongst midwives due to a range of barriers. This study aimed to evaluate United Kingdom's midwives' current role and knowledge regarding the provision of PA advice to pregnant and postpartum women and identify the barriers and potential solutions., Methods: Ten UK midwives (mean work experience ± SD: 15.5 years ± 10.2) participated in semi-structured interviews between May and July 2023. Data were analysed using a deductive thematic approach following Braun and Clarke's six steps. Demographic data were collected by Microsoft Forms then summarised using Microsoft Excel., Results: Six themes with 25 subthemes were identified as barriers and solutions in delivering PA advice. The role of midwives in providing PA advice during pregnancy; the role of midwives in providing PA advice postpartum; intrinsic barriers that limit PA advice provision (confidence, safety concerns, knowledge, and midwife's personal body habitus); extrinsic barriers that limit PA advice provision (lack of time, education, PA not a priority in care); solutions to allow midwives to promote PA (including formal PA education, and dissemination of resources); and optimising delivery of PA advice (personalized approach, interprofessional collaboration, and linking to mental health benefits)., Discussion: Midwives consider themselves ideally placed to provide PA advice to pregnant women, with many aware of the benefits PA provides. Despite this, there is a lack of PA advice provision and knowledge of PA guidelines. Postpartum PA advice appeared to be considered outside the remit of midwives, due to limited contact. Further research is needed to determine the current level of PA advice provision for pregnant and postpartum women and explore the role of other healthcare professionals involved in maternity care., 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., (© 2024 Mitra, Marino, Vishnubala, Pringle and Nykjaer.)

We investigated the effect of exercise intensity and tolerable duration on the development of exercise-induced diaphragm and expiratory muscle fatigue. Ten healthy adults (25 ± 5 yr; 2 females) cycled to intolerance on three separate occasions: 1 ) 5% below critical power (tw ) and gastric (Pga tw ) twitch pressures, respectively. Exercise time was 34.5 ± 6.2 min, 10.2 ± 2.6 min, and 4.9 ± 0.7 min for 2 ) at end-exercise was lower during 2peak ) relative to Δ25 (97 ± 4% V̇o 2peak ) and Δ50 (99 ± 4% V̇o 2peak ) ( P < 0.001). The pre- to postexercise decrease in Pdi tw was greater after Δ25 (-22 ± 12%) versus tw from pre- to postexercise was not different between trials ( 0.05). In conclusion, the magnitude of exercise-induced diaphragm fatigue was greater after longer-duration severe exercise than after shorter-duration severe and heavy exercise. By contrast, the magnitude of exercise-induced expiratory muscle fatigue was unaffected by exercise intensity and tolerable duration. NEW & NOTEWORTHY Exercise-induced respiratory muscle fatigue contributes to limiting exercise tolerance. Accordingly, better understanding the exercise conditions under which respiratory muscle fatigue occurs is warranted. Although heavy-intensity as well as short- and long-duration severe-intensity exercise performed to intolerance elicit diaphragm and expiratory muscle fatigue, we find, for the first time, that the relationship between exercise intensity, exercise duration, and the magnitude of exercise-induced fatigue is different for the diaphragm compared with the expiratory muscles.