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CaV2.1 mediates presynaptic dysfunction induced by amyloid β oligomers.
Synaptic dysfunction is an early pathological phenotype of Alzheimer's disease (AD) that is initiated by oligomers of amyloid β peptide (Aβos). Treatments aimed at correcting synaptic dysfunction could be beneficial in preventing disease progression, but mechanisms underlying Aβo-induced synaptic defects re…
Development of a fluorescence-based assay for RecBCD activity using Functional Data Analysis and Design of Experiments
Biochemical assays are essential tools in biological research and drug discovery, but optimisation of these assays is often a challenging and lengthy process due to the wide range of input...
Comprehensive analysis of SLC17A5 variants in large European cohorts reveals no association with Parkinson's disease risk.
BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron loss and α-synuclein aggregation. Aging is the primary risk factor, with both rare and common genetic variants playing a role. Previous studies have implicated lysosomal storage disorder (LSD)-relat…
Altered glycolysis triggers impaired mitochondrial metabolism and mTORC1 activation in diabetic β-cells.
Chronic hyperglycaemia causes a dramatic decrease in mitochondrial metabolism and insulin content in pancreatic β-cells. This underlies the progressive decline in β-cell function in diabetes. However, the molecular mechanisms by which hyperglycaemia produces these effects remain unresolved. Using isolat…
Physiological Function of Cyclic Nucleotide Phosphodiesterases in Atrial Myocytes and their Potential as Targets in Atrial Fibrillation.
Cyclic nucleotide hy drolysing phosphodiesterases (PDEs) are key regulators of cyclic nucleotide (e.g. cAMP and cGMP) signalling. Here we examine the role of PDEs in the physiology of atrial myocytes (AMs), the pathogenesis of atrial fibrillation (AF) and the potential of PDEs as therapeutic targets for AF. PDE1-5 an…
Circulating neuropeptide Y dynamics and performance during exercise in heart failure patients with contemporary medical and device therapy.
High cardiac sympathetic drive and release of the sympathetic cotransmitter neuropeptide Y (NPY) are significant features of congestive heart failure (CHF), in which resting venous NPY levels are known to be associated with mortality. However, whether circulating NPY levels increase during exercise in CHF whe…
Sleep-wake-related changes in intracellular chloride regulate plasticity at glutamatergic cortical synapses.
Wakefulness and sleep affect the brain's ability to exhibit plastic changes.1,2 For instance, the potentiation of cortical excitatory synaptic connections is associated with the active period, when animals are mainly awake.3,4,5,6,7 It is unclear, however, how changes in neuronal physiology that are associated…
Unique pathways downstream of TLR-4 and TLR-7 activation: sex-dependent behavioural, cytokine, and metabolic consequences.
INTRODUCTION: Post-infection syndromes are characterised by fatigue, muscle pain, anhedonia, and cognitive impairment; mechanistic studies exploring these syndromes have focussed on pathways downstream of Toll-like receptor (TLR) 4 activation. Here, we investigated the mechanistic interplay between…
TPC2 in drug development: Emerging target for cancer, viral infections, cardiovascular diseases, and neurological disorders.
The lysosomal two-pore channel 2 (TPC2) modulates intracellular calcium (Ca2 +) signaling and has been implicated in inflammatory, cardiovascular, and neurodegenerative conditions, as well as cancer and viral infections. Despite its potential as a drug target, TPC2 is still in the early stages of therapeutic dev…
Glucokinase activity in diabetes: too much of a good thing?
Type 2 diabetes (T2D) is a global health problem characterised by chronic hyperglycaemia due to inadequate insulin secretion. Because glucose must be metabolised to stimulate insulin release it was initially argued that drugs that stimulate glucokinase (the first enzyme in glucose metabolism) would enhanc…
Period3 modulates the NAD+-SIRT3 axis to alleviate depression-like behaviour by enhancing NAMPT activity in mice.
INTRODUCTION: PER3 deficiency is associated with depression-like behaviors, but the underlying mechanisms remain unclear. OBJECTIVES: This study aims to elucidate the role and mechanism of PER3 in regulating depression-like behaviors in mice. METHODS: Depression-like behaviors were assessed using the su…
The role of electroencephalography in epilepsy research-From seizures to interictal activity and comorbidities.
Electroencephalography (EEG) has been instrumental in epilepsy research for the past century, both for basic and translational studies. Its contributions have advanced our understanding of epilepsy, shedding light on the pathophysiology and functional organization of epileptic networks, and the mechanisms und…
More and Less Fear in Serotonin Transporter Knockout Mice.
Recent theories suggest that reduced serotonin transporter (5-HTT) function, which increases serotonin (5-HT) levels at the synapse, enhances neural plasticity and affects sensitivity to environmental cues. This may promote learning about emotionally relevant events. However, the boundaries that define…