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Under pressure: UK preclinical neuroscience at a crossroads.
Graphical Abstract.
The "TASK" of Breathing: Anesthetic Relevance of Background Two-Pore Domain Potassium Channels as Therapeutic Targets for Respiratory Control.
Background (leak) potassium (K+) currents, the main contributors to resting membrane potential in excitable cells, are mediated by channels of the 2-pore domain (K2P) family. In the respiratory system, the TWIK-related acid-sensitive K+ channel (TASK) subfamily is proposed to mediate key functions in the carotid body type I glomus cells, central chemoreceptors and respiratory center, pulmonary arteries, and upper airway musculature. K2P channels are also located throughout the central nervous system, notably in the hypoglossal motor neurone pool, regions involved in sleep-wake regulation and pain perception. Being sensitive to general anesthetics, K2P channels may mediate both the adverse respiratory effects and hypnotic actions of many anesthetics. Therefore, they offer potential as pharmacological targets to reverse postoperative respiratory depression, ameliorate anesthetic risks of obstructive sleep apnea, improve ventilation-perfusion matching, and even assist in the active recovery from hypnotic effects of anesthesia during emergence from surgery.
Augmenting rehabilitation robotics with spinal cord neuromodulation: A proof of concept.
Rehabilitation robotics aims to promote activity-dependent reorganization of the nervous system. However, people with paralysis cannot generate sufficient activity during robot-assisted rehabilitation and, consequently, do not benefit from these therapies. Here, we developed an implantable spinal cord neuroprosthesis operating in a closed loop to promote robust activity during walking and cycling assisted by robotic devices. This neuroprosthesis is device agnostic and designed for seamless implementation by nonexpert users. Preliminary evaluations in participants with paralysis showed that the neuroprosthesis enabled well-organized patterns of muscle activity during robot-assisted walking and cycling. A proof-of-concept study suggested that robot-assisted rehabilitation augmented by the neuroprosthesis promoted sustained neurological improvements. Moreover, the neuroprosthesis augmented recreational walking and cycling activities outdoors. Future clinical trials will have to confirm these findings in a broader population.
Brain aging shows nonlinear transitions, suggesting a midlife "critical window" for metabolic intervention.
Understanding the key drivers of brain aging is essential for effective prevention and treatment of neurodegenerative diseases. Here, we integrate human brain and physiological data to investigate underlying mechanisms. Functional MRI analyses across four large datasets (totaling 19,300 participants) show that brain networks not only destabilize throughout the lifetime but do so along a nonlinear trajectory, with consistent temporal "landmarks" of brain aging starting in midlife (40s). Comparison of metabolic, vascular, and inflammatory biomarkers implicate dysregulated glucose homeostasis as the driver mechanism for these transitions. Correlation between the brain's regionally heterogeneous patterns of aging and gene expression further supports these findings, selectively implicating GLUT4 (insulin-dependent glucose transporter) and APOE (lipid transport protein). Notably, MCT2 (a neuronal, but not glial, ketone transporter) emerges as a potential counteracting factor by facilitating neurons' energy uptake independently of insulin. Consistent with these results, an interventional study of 101 participants shows that ketones exhibit robust effects in restabilizing brain networks, maximized from ages 40 to 60, suggesting a midlife "critical window" for early metabolic intervention.
Memories or decisions? Bridging accounts of frontopolar function.
Frontopolar cortex (FPC), for a long time elusive to functional description, is now associated with a wide range of cognitive processes. Prominent accounts of FPC function emerged from studies of memory (e.g., episodic and prospective memory; EM and PM, respectively) and of executive function (e.g., planning, multi-tasking, relational reasoning, cognitive branching, etc). In recent years, FPC function has begun to be described within the context of value-based decision making in terms of monitoring the value of alternatives and optimizing cognitive resources to balance the explore/exploit dilemma in the face of volatile environments. In this perspective, we propose that the broad counterfactual inference and behavioural flexibility account can help re-interpret findings from EM and PM studies and offer an explanatory bridge between the memory and executive function accounts. More specifically, we propose that counterfactual value monitoring in FPC modulates the reallocation of cognitive resources between present and past information and contributes to efficient episodic and prospective retrieval by concurrently assessing the value of competing memories in relation to the decision at hand and proactively evaluating future potential scenarios to anticipate optimal engagement of intentions.
Cyclic nucleotide phosphodiesterases as drug targets.
Cyclic nucleotides are synthesized by adenylyl and/or guanylyl cyclase, and downstream of this synthesis, the cyclic nucleotide phosphodiesterase families (PDEs) specifically hydrolyze cyclic nucleotides. PDEs control cyclic adenosine-3',5'monophosphate (cAMP) and cyclic guanosine-3',5'-monophosphate (cGMP) intracellular levels by mediating their quick return to the basal steady state levels. This often takes place in subcellular nanodomains. Thus, PDEs govern short-term protein phosphorylation, long-term protein expression, and even epigenetic mechanisms by modulating cyclic nucleotide levels. Consequently, their involvement in both health and disease is extensively investigated. PDE inhibition has emerged as a promising clinical intervention method, with ongoing developments aiming to enhance its efficacy and applicability. In this comprehensive review, we extensively look into the intricate landscape of PDEs biochemistry, exploring their diverse roles in various tissues. Furthermore, we outline the underlying mechanisms of PDEs in different pathophysiological conditions. Additionally, we review the application of PDE inhibition in related diseases, shedding light on current advancements and future prospects for clinical intervention. SIGNIFICANCE STATEMENT: Regulating PDEs is a critical checkpoint for numerous (patho)physiological conditions. However, despite the development of several PDE inhibitors aimed at controlling overactivated PDEs, their applicability in clinical settings poses challenges. In this context, our focus is on pharmacodynamics and the structure activity of PDEs, aiming to illustrate how selectivity and efficacy can be optimized. Additionally, this review points to current preclinical and clinical evidence that depicts various optimization efforts and indications.
Population genomics of Marchantia polymorpha subsp. ruderalis reveals evidence of climate adaptation
Sexual reproduction results in the development of haploid and diploid cell states during the life cycle. In bryophytes, the dominant multicellular haploid phase produces motile sperm that swim through water to the egg to effect fertilization from which a relatively small diploid phase develops. In angiosperms, the reduced multicellular haploid phase produces non-motile sperm that is delivered to the egg through a pollen tube to effect fertilization from which the dominant diploid phase develops. These different life cycle characteristics are likely to impact the distribution of genetic variation among populations. However, little is known about the distribution of genetic variation among wild populations of bryophytes. To investigate how genetic variation is distributed among populations of a bryophyte and to establish the foundation for population genetics research in bryophytes, we described the genetic diversity of collections of Marchantia polymorpha subsp. ruderalis, a cosmopolitan ruderal liverwort. We identified 78 genetically unique (non-clonal) from a total of 209 sequenced accessions collected from 37 sites in Europe and Japan. There was no detectable population structure among European populations but significant genetic differentiation between Japanese and European populations. By associating genetic variation across the genome with global climate data, we showed that temperature and precipitation influence the frequency of potentially adaptive alleles. This collection establishes the core of an experimental platform that exploits natural genetic variation to answer diverse questions in biology.
Immune evasion runs in the family: two surface protein families of Plasmodium falciparum-infected erythrocytes.
Two protein families are found on the surfaces of erythrocytes infected with Plasmodium falciparum, a causative agent of deadly malaria. PfEMP1 are tethers binding endothelial receptors and holding infected erythrocytes to tissue and blood vessel surfaces, away from splenic clearance. RIFINs interact with immune receptors on natural killer cells, suppressing infected erythrocyte destruction. Both have expanded into families of diverse members to allow antigenic variation but retain surfaces of conserved chemistry and shape to bind human receptors. Recently discovered broadly inhibitory antibodies target one such surface on many EPCR-binding PfEMP1. Remarkable antibodies take this one step further, directly incorporating ectodomains of immune receptors into their loops, allowing RIFIN recognition. Finally, some RIFINs are targets of activating killer immune receptors, helping natural killer cells destroy infected erythrocytes. Studies of these two families therefore reveal a snapshot of the battle between this ancient parasite and the immune system of its human host.
Drug repurposing in amyotrophic lateral sclerosis (ALS).
INTRODUCTION: Identifying treatments that can alter the natural history of amyotrophic lateral sclerosis (ALS) is challenging. For years, drug discovery in ALS has relied upon traditional approaches with limited success. Drug repurposing, where clinically approved drugs are reevaluated for other indications, offers an alternative strategy that overcomes some of the challenges associated with de novo drug discovery. AREAS COVERED: In this review, the authors discuss the challenge of drug discovery in ALS and examine the potential of drug repurposing for the identification of new effective treatments. The authors consider a range of approaches, from screening in experimental models to computational approaches, and outline some general principles for preclinical and clinical research to help bridge the translational gap. Literature was reviewed from original publications, press releases and clinical trials. EXPERT OPINION: Despite remaining challenges, drug repurposing offers the opportunity to improve therapeutic options for ALS patients. Nevertheless, stringent preclinical research will be necessary to identify the most promising compounds together with innovative experimental medicine studies to bridge the translational gap. The authors further highlight the importance of combining expertise across academia, industry and wider stakeholders, which will be key in the successful delivery of repurposed therapies to the clinic.
Prevalence of dementia risk factors in the Oxford Brain Health Clinic.
With promising disease-modifying therapies (DMTs) emerging and good evidence to support risk reduction in the delay of dementia onset and progression, it is important to understand the profile of patients attending memory assessment services to estimate what proportion of patients might benefit from different types of interventions. The Oxford Brain Health Clinic (OBHC) is a psychiatry-led, clinical-research service that offers memory clinic patients detailed clinical assessments and equal access to research opportunities as part of their secondary care pathway. In this work, we describe the characteristics of OBHC patients in terms of demographics, diagnoses and prevalence of potentially modifiable risk factors compared with a cohort of healthy volunteers and the average memory clinic population. Our results suggest that high research consent rates (91.5%) in the OBHC resulted in a highly representative cohort of the clinical population. Based on Lecanemab trial inclusion criteria, 24.6% of the OBHC population may be suitable for further investigation into DMTs. Furthermore, 67.4% of OBHC patients have at least one potentially modifiable risk factor that may benefit from lifestyle interventions, particularly those focused on depression, sleep and physical activity.
Rational Design, Synthesis, and Evaluation of Novel Polypharmacological Compounds Targeting NaV1.5, KV1.5, and K2P Channels for Atrial Fibrillation.
Atrial fibrillation (AF) involves electrical remodeling of the atria, with ion channels such as NaV1.5, KV1.5, and TASK-1 playing crucial roles. This study investigates acetamide-based compounds designed as multi-target inhibitors of these ion channels to address AF. Compound 6f emerged as the most potent in the series, demonstrating a strong inhibition of TASK-1 (IC50 ∼0.3 μM), a moderate inhibition of NaV1.5 (IC50 ∼21.2 μM) and a subtle inhibition of KV1.5 (IC50 ∼81.5 μM), alongside unexpected activation of TASK-4 (∼40% at 100 μM). Functional assays on human atrial cardiomyocytes from sinus rhythm (SR) and AF patients revealed that 6f reduced action potential amplitude in SR (indicating NaV1.5 block), while in AF it increased action potential duration (APD), reflecting high affinity for TASK-1. Additionally, 6f caused hyperpolarization of the resting membrane potential in AF cardiomyocytes, consistent with the observed TASK-4 activation. Mathematical modeling further validated its efficacy in reducing AF burden. Pharmacokinetic analyses suggest favorable absorption and low toxicity. These findings identify 6f as a promising multi-target therapeutic candidate for AF management.
A systematic review of in vivo brain insulin resistance biomarkers in humans
Type 2 diabetes mellitus (T2DM) is associated with an elevated risk of dementia, prompting interest into the concept of brain-specific insulin resistance. However, the brain's reliance on insulin-independent glucose transporters complicates attempts to measure in vivo brain insulin resistance using the definition of system-wide insulin resistance, which is based on glucose-insulin interactions. In this review, we explore three available biomarkers for evaluating in vivo brain-specific insulin resistance in humans: (1) correlating systemic insulin resistance with brain function, (2) examining functional brain changes after the administration of intranasal insulin, and (3) quantifying insulin signalling proteins in neuronally enriched blood-derived extracellular vesicles. Integrating evidence from these three approaches tentatively suggests for the first time that a comprehensive assessment of the brain's default mode network (DMN), combining these methodologies within a single study, may offer a useful biomarker to quantify in vivo brain-specific insulin resistance in humans. Correlating DMN responses to concentrations of pY-IRS-1 in blood-derived extracellular vesicles would corroborate evidence for a brain-specific biomarker and provide a scalable approach to detecting brain-specific insulin resistance in humans. This advancement would enable in vivo evaluations of insulin resistance in the central nervous system, akin to the precise measurements of systemic insulin resistance seen in T2DM. An established and clearly defined biomarker of in vivo brain insulin resistance in humans would permit further investigation into the links between diabetes and dementia, ultimately bolstering support for secondary dementia prevention by identifying those at higher risk for cognitive decline.
Bryophytes as metabolic engineering platforms.
Metabolic engineering of plants offers significant advantages over many microbial systems such as cost-effective scalability and carbon autotrophy. Bryophytes have emerged as promising testbeds for plant metabolic engineering due to their rapid transformation and haploid-dominant lifecycle. The liverwort Marchantia polymorpha and the moss Physcomitrium patens are the best studied bryophytes and an expanding toolkit of genetic resources for both species allows for efficient pathway engineering. Bryophyte metabolism, while broadly conserved with seed plants, exhibits distinct features such as high diversity and amounts of terpenoids and very long-chain polyunsaturated fatty acids (vlcPFAs). In this review, we summarise the relatively limited understanding of bryophyte metabolism and how it diverges from seed plants. We argue that the success of bryophytes as testbed species will require new quantitative knowledge of fluxes in central metabolism and especially those that facilitate high rates of terpenoid and vlcPFA biosynthesis.
Changes in iPSC-Astrocyte morphology reflect Alzheimer's disease patient clinical markers.
Human induced pluripotent stem cells (iPSCs) provide powerful cellular models of Alzheimer's disease (AD) and offer many advantages over non-human models, including the potential to reflect variation in individual-specific pathophysiology and clinical symptoms. Previous studies have demonstrated that iPSC-neurons from individuals with Alzheimer's disease (AD) reflect clinical markers, including β-amyloid (Aβ) levels and synaptic vulnerability. However, despite neuronal loss being a key hallmark of AD pathology, many risk genes are predominantly expressed in glia, highlighting them as potential therapeutic targets. In this work iPSC-derived astrocytes were generated from a cohort of individuals with high versus low levels of the inflammatory marker YKL-40, in their cerebrospinal fluid (CSF). iPSC-derived astrocytes were treated with exogenous Aβ oligomers and high content imaging demonstrated a correlation between astrocytes that underwent the greatest morphology change from patients with low levels of CSF-YKL-40 and more protective APOE genotypes. This finding was subsequently verified using similarity learning as an unbiased approach. This study shows that iPSC-derived astrocytes from AD patients reflect key aspects of the pathophysiological phenotype of those same patients, thereby offering a novel means of modelling AD, stratifying AD patients and conducting therapeutic screens.
Why friendship and loneliness affect our health.
Humans, like all monkeys and apes, have an intense desire to be social. The human social world, however, is extraordinarily complex, depends on sophisticated cognitive and neural processing, and is easily destabilized, with dramatic consequences for our mental and physical health. To show why, I first summarize descriptive aspects of human friendships and what they do for us, then discuss the cognitive and neurobiological processes that underpin them. I then summarize the growing body of evidence suggesting that our mental as well as our physical health and wellbeing are best predicted by the number and quality of close friend/family relationships we have, with five being the optimal number. Finally, I review neurobiological evidence that both number of friends and loneliness itself are correlated with the volume of certain key brain regions associated with the default mode neural network and its associated gray-matter processing units.