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Changes in sensorimotor network dynamics in resting-state recordings in Parkinson's disease.
Non-invasive recordings of magnetoencephalography have been used for developing biomarkers for neural changes associated with Parkinson's disease that can be measured across the entire course of the disease. These studies, however, have yielded inconsistent findings. Here, we investigated whether analysing motor cortical activity within the context of large-scale brain network activity provides a more sensitive marker of changes in Parkinson's disease using magnetoencephalography. We extracted motor cortical beta power and beta bursts from resting-state magnetoencephalography scans of patients with Parkinson's disease (N = 28) and well-matched healthy controls (N = 36). To situate beta bursts in their brain network contexts, we used a time-delay-embedded hidden Markov model to extract brain network activity and investigated co-occurrence patterns between brain networks and beta bursts. Parkinson's disease was associated with decreased beta power in motor cortical power spectra, but no significant differences in motor cortical beta-burst dynamics occurred when using a conventional beta-burst analysis. Dynamics of a large-scale sensorimotor network extracted with the time-delay-embedded hidden Markov model approach revealed significant decreases in the occurrence of this network with Parkinson's disease. By comparing conventional burst and time-delay-embedded hidden Markov model state occurrences, we observed that motor beta bursts occurred during both sensorimotor and non-sensorimotor network activations. When using the large-scale network information provided by the time-delay-embedded hidden Markov model to focus on bursts that were active during sensorimotor network activations, significant decreases in burst dynamics could be observed in patients with Parkinson's disease. In conclusion, our findings suggest that decreased motor cortical beta power in Parkinson's disease is prominently associated with changes in sensorimotor network dynamics using magnetoencephalography. Thus, investigating large-scale networks or considering the large-scale network context of motor cortical activations may be crucial for identifying alterations in the sensorimotor network that are prevalent in Parkinson's disease and might help resolve contradicting findings in the literature.
The effects of lacosamide, pregabalin, and tapentadol on peripheral nerve excitability: A randomized, double-blind, placebo-controlled, crossover, multi-center trial in healthy subjects.
BACKGROUND: Chronic pain is a leading cause of disability globally, with limited treatment options and frequent adverse effects. The IMI-PainCare-BioPain project aimed to enhance analgesic drug development by standardizing biomarkers. This study, IMI2-PainCare-BioPain-RCT1, evaluated the effects of lacosamide, pregabalin, and tapentadol on peripheral nerve excitability in healthy subjects through a randomized, double-blind, placebo-controlled crossover trial. METHODS: The study included 43 healthy participants aged 18-45 years. Participants underwent four treatment periods where they received single doses of lacosamide (200 mg), pregabalin (150 mg), tapentadol (100 mg), or placebo. High-frequency stimulation was applied to induce hyperalgesia. The two primary endpoints were changes in Strength Duration Time Constant (SDTC) in large sensory and motor fibers between lacosamide and placebo periods at the first post-dose timepoint compared to baseline (60 min). Other predefined endpoints included recovery cycle, threshold electrotonus (TEd), and S2 accommodation as well as effects of pregabalin and tapentadol. RESULTS: Lacosamide statistically significantly reduced SDTC in large sensory fibers (mean reduction 0.04 (95% CI 0.01-0.08), p = 0.012) and in motor fibers (mean reduction 0.04 (95% CI 0.00-0.07), p = 0.039) but had no effect on small sensory fibers at the first timepoint compared to placebo. There were no effects of pregabalin and tapentadol on SDTC. Of other predefined endpoints, lacosamide produced statistically significant changes in subexcitability, S2 accommodation TEd(peak), and TEd40(Accom) in large sensory fibers. No statistically significant changes were observed in refractoriness, relative refractory period, or accommodation half-time at the first timepoint compared to placebo. CONCLUSIONS: This study demonstrates that nerve excitability testing can detect pharmacodynamic effects on large myelinated fibers in healthy subjects. Lacosamide statistically significantly reduced peripheral nerve excitability, particularly in large sensory fibers.
Defective Olfactomedin-2 connects adipocyte dysfunction to obesity.
Olfactomedin-2 (OLFM2) is a pleiotropic glycoprotein emerging as a regulator of energy homeostasis. We here show the expression of OLFM2 to be adipocyte-specific and inversely associated with obesity. OLFM2 levels increase during adipogenesis and are suppressed in inflamed adipocytes. Functionally, OLFM2 deficiency impairs adipocyte differentiation, while its over-production enhances the adipogenic transformation of fat cell progenitors. Loss and gain of function experiments revealed that OLFM2 modulates key metabolic and structural pathways, including PPAR signaling, citrate cycle, fatty acid degradation, axon guidance and focal adhesion in 3T3 cell lines and primary human adipocytes. On the molecular level, OLFM2 deficiency in differentiated adipocytes predominantly downregulates genes involved in cell cycle. Extending these findings in vivo, both whole-body Olfm2 knockout and adipose-specific Olfm2 depletion in mice resulted in impaired adipose cell cycle gene expression, with the latter also displaying fat mass accretion and metabolic dysfunction. Collectively, our results underscore a critical role for OLFM2 in adipocyte biology, and support a causative link between reduced adipose OLFM2 and the pathophysiology of obesity.
Compartmentalisation in cAMP signalling: A phase separation perspective.
Cells rely on precise spatiotemporal control of signalling pathways to ensure functional specificity. The compartmentalisation of cyclic AMP (cAMP) and protein kinase A (PKA) signalling enables distinct cellular responses within a crowded cytoplasmic space. Traditionally, compartmentalisation has been attributed to PKA anchoring, phosphodiesterase-mediated cAMP degradation, and restricted cAMP diffusion. Emerging evidence suggests that liquid-liquid phase separation (LLPS) can play a significant role in organising cAMP signalling. LLPS has been implicated in receptor clustering, cyclic nucleotide synthesis, effector activation, signal termination, and offers a dynamic mechanism for spatially restricting cAMP activity. Notably, PKA RIα condensates appear to act as cAMP reservoirs, modulating local cAMP availability and phosphodiesterase-mediated degradation. Disrupting LLPS-mediated condensation of cAMP/PKA pathway components has been linked to cancer and neurodegeneration, pointing to physiological relevance. This review explores current evidence of LLPS in cAMP signalling, highlighting implications for signal compartmentalisation and functional specificity.
Extracellular Vesicles as Targeted Communicators in Complementary Medical Treatments.
The supposed meridians of traditional oriental medicine have been a cause of conflict between traditional and modern medical science. A possible resolution has been proposed: That extracellular vesicles, including exosomes, may be the transmitters of traditional therapies such as massage and acupuncture. This article develops that idea by proposing that the pathways between surface and deep structures may be laid down during the embryonic migration of cells from one region of the developing body to distant regions. This hypothesis depends on the proven targeting of vesicular communication via cell surface binding molecules and their complementary binding sites on target cells. The hypothesis is therefore experimentally testable. The article also draws attention to a strong analogy with Charles Darwin's theory of pangenesis for particulate communication between the soma and germline.
How the Central Dogma and the Theory of Selfish Genes Misled Evolutionary and Medical Sciences in Understanding Multi-factorial Diseases
This synthesis article deconstructs the incorrect interpretations of the Central Dogma of Molecular Biology in popular accounts of Selfish Gene Theory in evolutionary biology and in genomics. “Selfish” in the theory is invalid whether interpreted literally or metaphorically. This deep misinterpretation of twentieth century biology, emphasising the primacy of genes in functionality, has encouraged the search for the genetic origins of major multi-factorial diseases, even in the face of continuing failure of genomics to provide the route to prediction or cures for those common fatal diseases. Reliance on The Human Genome Project for such cures has led medical science into an expensive impasse. It is time to bury the scientific dogmas of the twentieth century. There is no place in science for dogmas of any kind. What we need are functional therapies through understanding the functional networks that control genes and their evolution. We present a new diagrammatic way of representing the causal interactions between functional physiological networks and the chemical processes represented by the Central Dogma. It then becomes evident that there are many ways in which the activity and nucleotide composition of DNA can be varied.
Amyloid-β disrupts APP-regulated protein aggregation and dissociation from recycling endosomal membranes.
Secretory proteins aggregate into non-soluble dense-core granules in recycling endosome-like compartments prior to regulated release. By contrast, aberrantly processed, secreted amyloid-β (Aβ) peptides derived from amyloid precursor protein (APP) form pathological extracellular amyloidogenic aggregations in late-stage Alzheimer's disease (AD). By examining living Drosophila prostate-like secondary cells, we show that both APP and Aβ peptides affect normal biogenesis of dense-core granules. These cells generate dense-core granules and secreted nanovesicles called Rab11-exosomes via evolutionarily conserved mechanisms within highly enlarged secretory compartments with recycling endosomal identity. The fly APP homologue, APP-like (APPL), associates with these vesicles and the compartmental limiting membrane, from where its extracellular domain modulates protein aggregation. Proteolytic release of this domain permits mini-aggregates to coalesce into a large central dense-core granule. Mutant Aβ expression disrupts this process and compartment motility, and increases aberrant lysosomal targeting, mirroring previously unexplained early-stage pathological events in AD. It also promotes cell-to-cell propagation of these endolysosomal defects, again phenocopying changes observed in AD. Our data therefore demonstrate physiological roles for APP in membrane-dependent protein aggregation, involving molecular mechanisms, which when disrupted by Aβ peptides, trigger Alzheimer's disease-relevant pathologies.
Kir6.2 channel activity is regulated by interaction of transmembrane domains 1 and 2 through I167 in the bundle-crossing gate.
ATP-sensitive potassium (KATP) channel in pancreatic β-cells is composed of four pore-forming inward rectifier potassium (Kir) 6.2 subunits and four regulatory sulfonylurea receptor (SUR) 1 subunits and regulate insulin secretion. Kir6.2 consists of a N-terminal region, an outer transmembrane helix (TM1), an intramembrane region that functions as a potassium selectivity filter, an inner transmembrane helix (TM2) that forms a bundle-crossing gate, and a C-terminal cytoplasmic domain. Mutations in the Kir6.2 subunit can cause neonatal diabetes with severe neurological features (DEND syndrome). The DEND syndrome-inducing I167L mutation of Kir6.2 increases the open probability (Po) of the KATP channel. To investigate the gating mechanism impacted by this mutation in Kir6.2 alone, we used C-terminus-truncated Kir6.2 channels to ascertain the impact of I167 mutations on Po in Kir6.2 channels in the absence of SUR1. We found that I167L and I167F mutations showed an increased Po while the Po of other mutations (I167A, I167V) were unchanged when compared to wild-type channels. By mutating residues in TM1 (W68, L72, F75) that may interact with I167, we found that a double mutation of I167L and F75A normalized the Po. These results would suggest that I167 may play an important role in stabilizing the open state of Kir6.2 channels.
Mitochondrial origins of the pressure to sleep.
To gain a comprehensive, unbiased perspective on molecular changes in the brain that may underlie the need for sleep, we have characterized the transcriptomes of single cells isolated from rested and sleep-deprived flies. Here we report that transcripts upregulated after sleep deprivation, in sleep-control neurons projecting to the dorsal fan-shaped body1,2 (dFBNs) but not ubiquitously in the brain, encode almost exclusively proteins with roles in mitochondrial respiration and ATP synthesis. These gene expression changes are accompanied by mitochondrial fragmentation, enhanced mitophagy and an increase in the number of contacts between mitochondria and the endoplasmic reticulum, creating conduits3,4 for the replenishment of peroxidized lipids5. The morphological changes are reversible after recovery sleep and blunted by the installation of an electron overflow6,7 in the respiratory chain. Inducing or preventing mitochondrial fission or fusion8-13 in dFBNs alters sleep and the electrical properties of sleep-control cells in opposite directions: hyperfused mitochondria increase, whereas fragmented mitochondria decrease, neuronal excitability and sleep. ATP concentrations in dFBNs rise after enforced waking because of diminished ATP consumption during the arousal-mediated inhibition of these neurons14, which augments their mitochondrial electron leak7. Consistent with this view, uncoupling electron flux from ATP synthesis15 relieves the pressure to sleep, while exacerbating mismatches between electron supply and ATP demand (by powering ATP synthesis with a light-driven proton pump16) precipitates sleep. Sleep, like ageing17,18, may be an inescapable consequence of aerobic metabolism.
Accurate Paediatric Brain Tumour Classification Through Improved Quantitative Analysis of 1H MR Imaging and Spectroscopy.
Multimodality imaging is an emerging research topic in neuro-oncology for its potential of being able to demonstrate tumours in a more comprehensive manner. Diffusion-weighted magnetic resonance imaging (dMRI) and proton magnetic resonance spectroscopy (1H-MRS) allow inferring tissue cellularity and biochemical properties, respectively. Combining dMRI and 1H-MRS may provide more accurate diagnosis for paediatric brain tumours than only one modality. This retrospective study collected 1.5-T clinical 1H-MRS and dMRI from 32 patients to assess paediatric brain tumour classification with combined dMRI and 1H-MRS. Specifically, spectral noise of 1H-MRS was suppressed before calculating metabolite concentrations. Extracted radiomic features were apparent diffusion coefficient (ADC) histogram features through dMRI and metabolite concentrations through 1H-MRS. These features were put together and then ranked according to the multiclass area under the curve (mAUC) and selected for tumour classification through machine learning. Tumours were precisely typed by combining noise-suppressed 1H-MRS and dMRI, and the cross-validated accuracy was improved to be 100% according to naïve Bayes. The finally selected radiomic biomarkers, which showed the highest diagnostic ability, were ADC fifth percentile (mAUC = 0.970), myo-inositol (mAUC = 0.952), combined glutamate and glutamine (mAUC = 0.853), total creatine (mAUC = 0.837) and glycine (mAUC = 0.815). The study indicates combining MR imaging and spectroscopy can provide better diagnostic performance than single-modal imaging.
Immunoassay for pyruvate kinase M1/2 as an Alzheimer's biomarker in CSF.
Alzheimer's disease (AD) is characterized by amyloid-beta plaques and tau tangles in the brain, but these markers alone do not predict disease progression. The intersection of these pathologies with other processes including metabolic changes may contribute to disease progression. Brain glucose metabolism changes are among the earliest detectable events in AD. Pyruvate kinase (PKM) has been implicated as a potential biomarker to track these metabolic changes. We have developed an enzyme-linked immunosorbent assay (ELISA) to assess PKM levels in cerebrospinal fluid (CSF). First, we verified the relationship of CSF PKM levels with cognitive decline, revealing a correlation between elevated CSF PKM levels and accelerated cognitive decline in preclinical AD patients in a tau-dependent manner. We developed the ELISA using two PKM-specific antibodies and validated it through quality control steps, indicating robust quantification of PKM. We showed that ELISA measurements of PKM correlate with mass spectrometry values in matching samples. When tested on an independent cohort, the assay confirmed elevation of PKM in AD. These findings support the use of PKM as a potential biomarker for tracking early metabolic changes in AD, offering a novel tool for investigating metabolic alterations and their intersection with other underlying pathologies in AD progression.
Efficient in vivo targeting of the myocardial scar using Moloney murine leukaemia virus complexed with nanoparticles
AbstractDuring myocardial infarction, native myocardium is replaced by a fibrous scar, impairing cardiac pump function and leading to potentially life‐threatening ventricular tachycardias. Gene therapy‐based targeting of the cardiac scar is essential for short‐ and long‐term treatment of post‐infarct sequelae. However, there are currently no effective methods to target and transduce cardiac (myo)fibroblasts (FB) in vivo. Therefore, Moloney murine leukaemia virus (MMLV) encoding for the fluorescent reporter mCherry complexed with magnetic nanoparticles (MNP) in combination with magnetic steering was tested. This approach strongly increased the transduction rate of FB by four‐fold in vitro. Additionally, injection of MMLV/MNP complexes into the forming scar during exposure of the heart to a magnetic field to increase virus dwell‐time 3 days after left ventricular cryo‐injury, a time when FB proliferation in the infarct peaks, yielded efficient transduction of resident FB. We further assessed the functional impact of overexpressing the gap junction protein connexin 43 (Cx43). MMLV‐mediated Cx43 overexpression (MMLV‐Cx43) in FB increased the formation of functional gap junctions in vitro and substantially lowered post‐cryo‐injury ventricular tachycardia incidence (by 50%), as demonstrated by in vivo electrophysiological testing 2 and 8 weeks after MMLV/MNP injection into the lesion. This anti‐arrhythmic effect was probably the result of a decrease in the heterogeneity of conduction around and across the scar, as observed by optical mapping in isolated hearts overexpressing Cx43. Thus, MMLV/MNP complexes combined with magnetic steering offer an efficient strategy for targeting and transducing FB in vitro and in vivo, allowing modulation of the functional properties of cardiac scars. imageKey points Genetic targeting and efficient transduction of (myo)fibroblasts (FB) in vivo are necessary to modify the properties of cardiac scars for therapeutic benefit. However, this has proven highly inadequate because of a lack of suitable viral vectors. We complexed Moloney murine leukaemia virus (MMLV) with magnetic nanoparticles (MNP) and applied a magnetic field to achieve prominent in vitro transduction of FB. Magnet‐assisted in vivo injections of MMLV/MNP complexes into the developing scar enabled efficient transduction of cardiac tissue‐resident FB. MMLV‐Cx43‐based overexpression of connexin 43 increased the density of functional gap junctions in FB in vitro. Following direct injection of the virus into the developing cardiac scar in a murine cryo‐lesion model, electrophysiological in vivo testing showed that the incidence of ventricular tachycardia was reduced by 50% at 2 and 8 weeks post‐treatment with MMLV. Our approach enables efficient targeting and transduction of FB in the cardiac scar, providing a blueprint for translation.
A missense mutation in zinc finger homeobox‐3 (ZFHX3) impedes growth and alters metabolism and hypothalamic gene expression in mice
AbstractA protein altering variant in the gene encoding zinc finger homeobox‐3 (ZFHX3) has recently been associated with lower BMI in a human genome‐wide association study. We investigated metabolic parameters in mice harboring a missense mutation in Zfhx3 (Zfhx3Sci/+) and looked for altered in situ expression of transcripts that are associated with energy balance in the hypothalamus to understand how ZFHX3 may influence growth and metabolic effects. One‐year‐old male and female Zfhx3Sci/+ mice weighed less, had shorter body length, lower fat mass, smaller mesenteric fat depots, and lower circulating insulin, leptin, and insulin‐like growth factor‐1 (IGF1) concentrations than Zfhx3+/+ littermates. In a second cohort of 9–20‐week‐old males and females, Zfhx3Sci/+ mice ate less than wildtype controls, in proportion to body weight. In a third cohort of female‐only Zfhx3Sci/+ and Zfhx3+/+ mice that underwent metabolic phenotyping from 6 to 14 weeks old, Zfhx3Sci/+ mice weighed less and had lower lean mass and energy expenditure, but fat mass did not differ. We detected increased expression of somatostatin and decreased expression of growth hormone‐releasing hormone and growth hormone‐receptor mRNAs in the arcuate nucleus (ARC). Similarly, ARC expression of orexigenic neuropeptide Y was decreased and ventricular ependymal expression of orphan G protein‐coupled receptor Gpr50 was decreased. We demonstrate for the first time an energy balance effect of the Zfhx3Sci mutation, likely by altering expression of key ARC neuropeptides to alter growth, food intake, and energy expenditure.
Decreasing HepG2 Cytotoxicity by Lowering the Lipophilicity of Benzo[d]oxazolephosphinate Ester Utrophin Modulators.
Utrophin modulation is a disease-modifying therapeutic strategy for Duchenne muscular dystrophy that would be applicable to all patient populations. To improve the suboptimal profile of ezutromid, the first-in-class clinical candidate, a second generation of utrophin modulators bearing a phosphinate ester moiety was developed. This modification significantly improved the physicochemical and ADME properties, but one of the main lead molecules was found to have dose-limiting hepatotoxicity. In this work we describe how less lipophilic analogues retained utrophin modulatory activity in a reporter gene assay, upregulated utrophin protein in dystrophic mouse muscle cells, but also had improved physicochemical and ADME properties. Notably, ClogP was found to directly correlate with pIC50 in HepG2 cells, hence leading to a potentially safer toxicological profiles in this series. Compound 21 showed a balanced profile (H2K EC50: 4.17 μM, solubility: 477 μM, mouse hepatocyte T 1/2 > 240 min) and increased utrophin protein 1.6-fold in a Western blot assay.