Journal of Physiology-London最新文献

{"title":"CSF1-R inhibition attenuates posttraumatic osteoarthritis and quadriceps atrophy following ligament injury.","authors":"Alexander R Keeble, Nicholas T Thomas, Peyton J Balawender, Camille R Brightwell, Sara Gonzalez-Velez, Madeline G O'Daniel, Caitlin E Conley, Austin V Stone, Darren L Johnson, Brian Noehren, Cale A Jacobs, Christopher S Fry, Allison M Owen","doi":"10.1113/JP286815","DOIUrl":"https://doi.org/10.1113/JP286815","url":null,"abstract":"<p><p>Knee osteoarthritis contributes substantially to worldwide disability. Post-traumatic osteoarthritis (PTOA) develops secondary to joint injury, such as ligament rupture, and there is increasing evidence suggesting a key role for inflammation in the aetiology of PTOA and associated functional deficits. Colony stimulating factor 1 receptor (CSF1-R) has been implicated in the pathogenesis of musculoskeletal degeneration following anterior cruciate ligament (ACL) injury. We sought to assess the efficacy of CSF1-R inhibition to mitigate muscle and joint pathology in a mouse model of PTOA. Four-month-old mice were randomized to receive a CSF1-R inhibitor and studied for 7 or 28 days after joint injury. Additionally, we profiled synovial fluid samples for CSF1-R from patients with injury to their ACL. Transcriptomic analysis of quadriceps muscle and articular cartilage in CSF1-R inhibitor-treated animals at 7 days after injury revealed elevated chondrocyte differentiation within articular cartilage and enhanced metabolic and contractile gene expression within skeletal muscle. At 28 days post-injury, CSF1-R inhibition attenuated PTOA severity and mitigated skeletal muscle atrophy. Patient synovial fluid CSF1-R levels correlated with matrix metalloproteinase 13, a prognostic marker and molecular effector of PTOA. Our findings support an opportunity for CSF1-R targeting to mitigate the severity of PTOA and muscle atrophy after joint injury. KEY POINTS: Posttraumatic osteoarthritis (PTOA) of the knee commonly results from direct injury to the joint, which is characterized by pain, weakness, and disability. Induction of colony stimulating factor one receptor (CSF1-R) is positively associated with knee trauma severity, and the initial acute inflammatory state suppresses muscle recovery and degrades articular cartilage. Skeletal muscle and articular cartilage transcriptomic response following direct joint injury in a murine model of PTOA is rescued by pharmacological inhibition of CSF1-R. CSF1-R inhibition mitigated skeletal muscle atrophy and attenuated PTOA severity and synovitis. Patient synovial fluid CSF1-R levels correlated with matrix metalloproteinase 13, a prognostic marker and molecular effector of PTOA, offering further evidence for CSF1-R as a therapeutic target across musculoskeletal tissues after injury.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142873337","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Electrical stimulation of injured nerves promotes recovery in animals and humans.","authors":"Tessa Gordon","doi":"10.1113/JP286566","DOIUrl":"https://doi.org/10.1113/JP286566","url":null,"abstract":"<p><p>The frequent poor functional outcomes after delayed surgical repair of injured human peripheral nerves results in progressive downregulation of growth-associated genes in parallel with reduced neuronal regenerative capacity under each of the experimental conditions of chronic axotomy of neurones that remain without target contact, chronic distal nerve stump denervation, and chronic muscle denervation. Brief (1 h) low-frequency (20 Hz) electrical stimulation (ES) accelerates the outgrowth of regenerating axons across the surgical site of microsurgical repair of a transected nerve. Exercise programmes also promote nerve regeneration with the combination of ES and exercise being the most effective. An ES conditioning lesion of intact nerve (CES) accelerates both axonal outgrowth and regeneration rate after the surgical repair of a more distal injury to the nerve, in contrast to ES of a repaired injury nerve that accelerates only the axon outgrowth. A CES accelerates both axonal outgrowth and regeneration rate after the surgical repair of a more distal injury to the nerve, in contrast to ES of a repaired injury nerve that accelerates only the axon outgrowth. The loss of contractility of permanently denervated muscles in cauda equinae-injured patients with accompanying severe loss of muscle mass, disarray of thick and thin contractile filaments, and disorganization of the sarcoplasmic reticulum that controls calcium delivery to the filaments, is alleviated by a 2-year programme of daily ES of the quadriceps muscle. These findings hold promise for recovery and rehabilitation in patients who suffer injury to the neuromuscular system. KEY POINTS: Poor functional outcomes after delayed surgical repair of injured human peripheral nerves are replicated by chronic neuronal axotomy, Schwann cell denervation in a nerve autograft, and muscle denervation. Exponential decline in expression of growth-associated genes accompanies the same decline in regenerative capacity. Brief (1 h) low-frequency (20 Hz) electrical stimulation (ES) that generates action potential conduction to the neuronal soma accelerates the outgrowth of regenerating axons across the surgical repair site of the transected nerve, even after delayed surgery. The same ES regimen accelerates muscle reinnervation in patients with chronic nerve injury who undergo carpal tunnel syndrome release surgery. A 2-year programme of daily ES of permanently denervated quadriceps muscles in cauda equinae-injured patients reinstated their contractility and organization.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142873339","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-ionotropic NMDAR signalling activates Panx1 to induce P2X4R-dependent long-term depression in the hippocampus.","authors":"Allison C Nielsen, Connor L Anderson, Carina Ens, Andrew K J Boyce, Roger J Thompson","doi":"10.1113/JP285193","DOIUrl":"https://doi.org/10.1113/JP285193","url":null,"abstract":"<p><p>In recent years, evidence supporting non-ionotropic signalling by the NMDA receptor (niNMDAR) has emerged, including roles in long-term depression (LTD). Here, we investigated whether niNMDAR-pannexin-1 (Panx1) contributes to LTD at the CA3-CA1 hippocampal synapse. Using whole-cell, patch clamp electrophysiology in rat hippocampal slices, we show that a low-frequency stimulation (3 Hz) of the Schaffer collaterals produces LTD that is blocked by continuous but not transient application of the NMDAR competitive antagonist, MK-801. After transient MK-801, LTD involved pannexin-1 and sarcoma (Src) kinase. We show that pannexin-1 is not permeable to Ca²⁺, but probably releases ATP to induce LTD via P2X4 purinergic receptors because LTD after transient MK-801 application was prevented by 5-BDBD. Thus, we conclude that niNMDAR activation of Panx1 can link glutamatergic and purinergic pathways to produce LTD following low frequency synaptic stimulation when NMDARs are transiently inhibited. KEY POINTS: Differential effect of short-term D-APV and MK-801 application on long-term depression (LTD) suggests that the NMDA receptor (niNMDAR) contributes to later phases of synaptic depression. niNMDAR LTD involved sarcoma (Src) kinase and pannexin-1 (Panx1), which is a pathway previously identified to be active during excitotoxicity. Panx1 was not calcium permeable but may contribute to late phase LTD via ATP release. Panx1 blockers prevent LTD, and this was rescued with exogenous ATP application. Inhibition of LTD with 5-BDBD suggests the downstream involvement of postsynaptic P2X4 receptors.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142873409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Recent advances in the structure, function and regulation of the volume-regulated anion channels and their role in immunity.","authors":"Sergei Yanushkevich, Aleksandra Zieminska, Joshua Gonzalez, Francisca Añazco, Richard Song, Alejandra Arias-Cavieres, Sara T Granados, Junyi Zou, Yan Rao, Axel R Concepcion","doi":"10.1113/JP285200","DOIUrl":"https://doi.org/10.1113/JP285200","url":null,"abstract":"<p><p>Volume-regulated anion channels (VRACs) are heteromeric complexes formed by proteins of the leucine-rich repeat-containing 8 (LRRC8) family. LRRC8A (also known as SWELL1) is the core subunit required for VRAC function, and it must combine with one or more of the other paralogues (i.e. LRRC8B-E) to form functional heteromeric channels. VRACs were discovered in T lymphocytes over 35 years ago and are found in virtually all vertebrate cells. Initially, these anion channels were characterized for their role in Cl^- efflux during the regulatory volume decrease process triggered when cells are subjected to hypotonic challenges. However, substantial evidence suggests that VRACs also transport small molecules under isotonic conditions. These findings have expanded the research on VRACs to explore their functions beyond volume regulation. In innate immune cells, VRACs promote inflammation by modulating the transport of immunomodulatory cyclic dinucleotides, itaconate and ATP. In adaptive immune cells, VRACs suppress their function by taking up cyclic dinucleotides to activate the STING signalling pathway. In this review, we summarize the current understanding of LRRC8 proteins in immunity and discuss recent progress in their structure, function, regulation and mechanisms for channel activation and gating. Finally, we also examine potential immunotherapeutic applications of VRAC modulation.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-12-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142873411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Corticolimbic structures activation during preparation and execution of respiratory manoeuvres in voluntary olfactory sampling: An intracranial EEG study.","authors":"Jules Granget, Marie Cécile Niérat, Katia Lehongre, Virginie Lambrecq, Valerio Frazzini, Vincent Navarro, Nathalie Buonviso, Thomas Similowski","doi":"10.1113/JP287045","DOIUrl":"https://doi.org/10.1113/JP287045","url":null,"abstract":"<p><p>Volitional respiratory manoeuvres such as sniffing and apnoea play a key role in the active olfactory exploration of the environment. Their impairment by neurodegenerative processes could thus impair olfactory abilities with the ensuing impact on quality of life. Functional brain imaging studies have identified brain networks engaged in sniffing and voluntary apnoea, comprising the primary motor and somatosensory cortices, the insula, the anterior cingulate cortex and the amygdala. The temporal organization and the oscillatory activities of these networks are not known. To elucidate these aspects, we recorded intracranial electroencephalograms in six patients during voluntary sniffs and short apnoeas (12 s). The preparation phase of both manoeuvres involved increased alpha and theta activity in the posterior insula, amygdala and temporal regions, with a specific preparatory activity in the parahippocampus for the short apnoeas and the hippocampus for sniff. Subsequently, it narrowed to the superior and median temporal areas, immediately after the manoeuvres. During short apnoeas, a particular dynamic was observed, consisting of a rapid decline in alpha and theta activity followed by a slow recovery and increase. Volitional respiratory manoeuvres involved in olfactory control involve corticolimbic structures in both a preparatory and executive manner. Further studies are needed to determine whether diseases altering deep brain structures can disrupt these mechanisms and if such disruption contributes to the corresponding olfactory deficits. KEY POINTS: Both sniff manoeuvres and short apnoeas are associated with oscillatory activity predominantly in low-frequency bands (alpha and theta). Preparation of sniff manoeuvres and short apnoeas involve activities in low-frequency bands in the posterior insula and temporal regions that extend to amygdala during the execution of both manoeuvres. During short apnoeas, activities in low-frequency bands initially decline before continuously increasing until the apnoeas end.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142866081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of presynaptic homeostatic plasticity by glial signalling in Alzheimer's disease.","authors":"Yimei Cai, Tingting Wang","doi":"10.1113/JP286751","DOIUrl":"https://doi.org/10.1113/JP286751","url":null,"abstract":"<p><p>Alzheimer's disease (AD), the most common form of dementia among the elderly, affects numerous individuals worldwide. Despite advances in understanding the molecular underpinnings of AD pathology, effective treatments to prevent or cure the disease remain elusive. AD is characterized not only by pathological hallmarks such as amyloid plaques and neurofibrillary tangles but also by impairments in synaptic physiology, circuit activity and cognitive function. Synaptic homeostatic plasticity plays a vital role in maintaining the stability of synaptic and neural functions amid genetic and environmental disturbances. A key component of this regulation is presynaptic homeostatic potentiation, where increased presynaptic neurotransmitter release compensates for reduced postsynaptic glutamate receptor functionality, thereby stabilizing neuronal excitability. The role of presynaptic homeostatic plasticity in synapse stabilization in AD, however, remains unclear. Moreover, recent advances in transcriptomics have illuminated the complex roles of glial cells in regulating synaptic function in ageing brains and in the progression of neurodegenerative diseases. Yet, the impact of AD-related abnormalities in glial signalling on synaptic homeostatic plasticity has not been fully delineated. This review discusses recent findings on how glial dysregulation in AD affects presynaptic homeostatic plasticity. There is increasing evidence that disrupted glial signalling, particularly through aberrant histone acetylation and transcriptomic changes in glia, compromises this plasticity in AD. Notably, the sphingosine signalling pathway has been identified as being protective in stabilizing synaptic physiology through epigenetic and homeostatic mechanisms, presenting potential therapeutic targets for treating neurodegenerative disorders.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142869786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of forelimb morphology in muscle sensorimotor functions during locomotion in the cat.","authors":"Seyed Mohammadali Rahmati, Alexander N Klishko, Ramaldo S Martin, Nate E Bunderson, Jeswin A Meslie, T Richard Nichols, Ilya A Rybak, Alain Frigon, Thomas J Burkholder, Boris I Prilutsky","doi":"10.1113/JP287448","DOIUrl":"https://doi.org/10.1113/JP287448","url":null,"abstract":"<p><p>Previous studies established strong links between morphological characteristics of mammalian hindlimb muscles and their sensorimotor functions during locomotion. Less is known about the role of forelimb morphology in motor outputs and generation of sensory signals. Here, we measured morphological characteristics of 46 forelimb muscles from six cats. These characteristics included muscle attachments, physiological cross-sectional area (PCSA) and fascicle length. We also recorded full-body mechanics and EMG activity of forelimb muscles during level overground and treadmill locomotion in seven and 16 adult cats of either sex, respectively. We computed forelimb muscle forces along with force- and length-dependent sensory signals mapped onto corresponding cervical spinal segments. We found that patterns of computed muscle forces and afferent activities were strongly affected by the muscle's moment arm, PCSA and fascicle length. Morphology of the shoulder muscles suggests distinct roles of the forelimbs in lateral force production and movements. Patterns of length-dependent sensory activity of muscles with long fibres (brachioradialis, extensor carpi radialis) closely matched patterns of overall forelimb length, whereas the activity pattern of biceps brachii length afferents matched forelimb orientation. We conclude that cat forelimb muscle morphology contributes substantially to locomotor function, particularly to control lateral stability and turning, rather than propulsion. KEY POINTS: Little is known about the role of forelimb muscle morphology in producing motor outputs and generating somatosensory signals. This information is needed to understand the contributions of forelimbs in locomotor control. We measured morphological characteristics of 46 muscles from cat forelimbs, recorded cat walking mechanics and electromyographic activity, and computed patterns of moment arms, length, velocity, activation, and force of forelimb muscles, as well as length- and force-dependent afferent activity during walking. We demonstrated that moment arms, physiological cross-sectional area and fascicle length of forelimb muscles contribute substantially to muscle force production and proprioceptive activity, to the regulation of locomotor cycle phase transitions and to control of lateral stability. The obtained information can guide the development of biologically accurate neuromechanical models of quadrupedal locomotion for exploring and testing novel methods of treatments of central nervous system pathologies by modulating activities in neural pathways controlling forelimbs/arms.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-12-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142865996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autonomic modulation with mindfulness-based stress reduction in chronic kidney disease: a randomized controlled trial.","authors":"Jinhee Jeong, Yingtian Hu, Matias Zanuzzi, Dana DaCosta, Jeann L Sabino-Carvalho, Sabrina Li, Jeanie Park","doi":"10.1113/JP287321","DOIUrl":"https://doi.org/10.1113/JP287321","url":null,"abstract":"<p><p>Chronic kidney disease (CKD) is characterized by overactivation of the sympathetic nervous system (SNS) that leads to increased risk of cardiovascular disease. This study was conducted to evaluate the effects of a Mindfulness-Based Stress Reduction (MBSR) programme on SNS activity in CKD patients. Participants with CKD stages III-IV were randomized to the 8 week MBSR programme or Health Enhancement Program (HEP; a structurally parallel, active control group). Intraneural measures of SNS activity directed to muscle [muscle sympathetic nerve activity (MSNA)] via microneurography was recorded at rest and during stress manoeuvres (mental arithmetic, handgrip exercise and cold pressor test). Data analyses were performed based on the intent-to-treat principle. In total, 29 participants (64 ± 9 years; 86% males) completed the intervention with 17 in the MBSR and 12 in the HEP groups. There was a significant Group (MBSR vs. HEP) by Time (baseline vs. post-intervention) interaction in MSNA reactivity to mental stress (P = 0.029), with a significant reduction in the mean ∆MSNA over 3 min of mental arithmetic at post-intervention (10.3 ± 4.2-5.9 ± 5.6 bursts/min, P < 0.001; Hedges' g = -0.858, 95% confidence interval [-1.578, -0.167]), while no change was observed within the HEP group (P = 0.818). Reduced ∆MSNA during handgrip exercise was also observed, while ∆MSNA during the cold pressor test and resting MSNA remained unchanged in both groups from baseline to post-intervention. In this randomized controlled trial, patients with CKD had a reduction of sympathetic reactivity during mental stress and static handgrip exercise following 8 weeks of MBSR but not after HEP. Our findings demonstrate that mindfulness training is feasible and may have clinically beneficial effects on autonomic function in CKD. KEY POINTS: Question: Does the Mindfulness-Based Stress Reduction (MBSR) programme reduce sympathetic activity in patients with chronic kidney disease (CKD)? Finding: In this randomized controlled trial including 29 patients with CKD, 8 weeks of MBSR decreased sympathetic reactivity to mental stress compared to the control Health Enhancement Program (HEP). Meaning: These finding suggest that mindfulness training may have clinically beneficial effects on autonomic function in CKD.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142856509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential effects of Phosphodiesterase 4A5 on cAMP-dependent forms of long-term potentiation.","authors":"Satya Murthy Tadinada, Emily N Walsh, Utsav Mukherjee, Ted Abel","doi":"10.1113/JP286801","DOIUrl":"https://doi.org/10.1113/JP286801","url":null,"abstract":"<p><p>cAMP signalling is critical for memory consolidation and certain forms of long-term potentiation (LTP). Phosphodiesterases (PDEs), enzymes that degrade the second messengers cAMP and cGMP, are highly conserved during evolution and represent a unique set of drug targets, given the involvement of these enzymes in several pathophysiological states including brain disorders. The PDE4 family of cAMP-selective PDEs exert regulatory roles in memory and synaptic plasticity, but the specific roles of distinct PDE4 isoforms in these processes are poorly understood. Building on our previous work demonstrating that spatial and contextual memory deficits were caused by expressing selectively the long isoform of the PDE4A subfamily, PDE4A5, in hippocampal excitatory neurons, we now investigate the effects of PDE4A isoforms on different cAMP-dependent forms of LTP. We found that PDE4A5 impairs long-lasting LTP induced by theta burst stimulation (TBS) while sparing long-lasting LTP induced by spaced four-train stimulation (4 × 100 Hz). This effect requires the unique N-terminus of PDE4A5 and is specific to this long isoform. Targeted overexpression of PDE4A5 in area CA1 is sufficient to impair TBS-LTP, suggesting that cAMP levels in the postsynaptic neuron are critical for TBS-LTP. Our results shed light on the inherent differences among the PDE4A subfamily isoforms, emphasizing the importance of the long isoforms, which have a unique N-terminal region. Advancing our understanding of the function of specific PDE isoforms will pave the way for developing isoform-selective approaches to treat the cognitive deficits that are debilitating aspects of psychiatric, neurodevelopmental and neurodegenerative disorders. KEY POINTS: Hippocampal overexpression of PDE4A5, but not PDE4A1 or the N-terminus-truncated PDE4A5 (PDE4A5Δ4), selectively impairs long-term potentiation (LTP) induced by theta burst stimulation (TBS-LTP). Expression of PDE4A5 in area CA1 is sufficient to cause deficits in TBS-LTP. Hippocampal overexpression of the PDE4A isoforms PDE4A1 and PDE4A5 does not impair LTP induced by repeated tetanic stimulation at the CA3-CA1 synapses. These results suggest that PDE4A5, through its N-terminus, regulates cAMP pools that are critical for memory consolidation and expression of specific forms of long-lasting synaptic plasticity at CA3-CA1 synapses.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142856514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhancing stroke risk stratification in atrial fibrillation through non-Newtonian blood modelling and Gaussian process emulation.","authors":"Paolo Melidoro, Abdel Rahman Amr Sultan, Ahmed Qureshi, Magdi H Yacoub, Khalil L Elkhodary, Gregory Y H Lip, Natalie Montarello, Nishant Lahoti, Ronak Rajani, Magdalena Klis, Steven E Williams, Oleg Aslanidi, Adelaide De Vecchi","doi":"10.1113/JP287283","DOIUrl":"https://doi.org/10.1113/JP287283","url":null,"abstract":"<p><p>Atrial fibrillation (AF) is the most common heart arrhythmia, linked to a five-fold increase in stroke risk. The left atrial appendage (LAA), prone to blood stasis, is a common thrombus formation site in AF patients. The LAA can be classified into four morphologies: broccoli, cactus, chicken wing and windsock. Stroke risk prediction in AF typically relies on demographic characteristics and comorbidities, often overlooking blood flow dynamics. We developed patient-specific non-Newtonian models of blood flow, dependent on fibrinogen and haematocrit, to predict changes in LAA viscosity, aiming to predict stroke in AF patients. We conducted 480 computational fluid dynamics (CFD) simulations using the non-Newtonian model across the four LAA morphologies for four virtual patient cohorts: AF + Covid-19, AF + pathological fibrinogen, AF + normal fibrinogen, and healthy controls. Gaussian process emulators (GPEs) were trained on this in silico cohort to predict average LAA viscosity at near-zero computational cost. GPEs demonstrated high accuracy in AF cohorts but lower accuracy when the chicken wing GPE was applied to other morphologies. Global sensitivity analysis showed fibrinogen significantly influenced blood viscosity in all AF cohorts. The chicken wing morphology exhibited the highest viscosity, while the AF + Covid-19 cohort had the highest viscosity. Our non-Newtonian model in CFD simulations confirmed fibrinogen's substantial impact on blood viscosity at low shear rates in the LAA, suggesting that combining blood values and geometric parameters of the LAA into GPE training could enhance stroke risk stratification accuracy. KEY POINTS: Fibrinogen has a significant effect on blood viscosity in the left atrial appendage (LAA) at low shear rates. Gaussian process emulators (GPEs) can predict the viscosity of blood in the LAA at near-zero computational cost. Out of all LAA morphologies, the chicken wing morphology exhibited the highest average blood viscosity. High average blood viscosity in the LAA of atrial fibrilation + Covid-19 patients was observed due to high fibrinogen levels in this cohort. Combining blood values and geometric parameters of the LAA into GPE training could enhance stroke risk stratification accuracy.</p>","PeriodicalId":50088,"journal":{"name":"Journal of Physiology-London","volume":" ","pages":""},"PeriodicalIF":4.7,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142848022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}