bluuebunny/crossref_metadata_2025_split huggingface dataset:
P2Y12 inhibitor monotherapy after short DAPT in acute coronary syndrome: a systematic review and meta-analysis
Authors: Galli Mattia , Laudani Claudio , Occhipinti Giovanni , Spagnolo Marco , Gragnano Felice , D'Amario Domenico , Navarese Eliano Pio , Mehran Roxana , Valgimigli Marco , Capodanno Davide , Angiolillo Dominick J 
Published: July 2024

Abstract

Background
P2Y12 inhibitor monotherapy after a short course of dual antiplatelet therapy (DAPT) may balance ischaemic and bleeding risks in patients with acute coronary syndrome (ACS). However, it remains uncertain how different P2Y12 inhibitors used as monotherapy affect outcomes.

Methods and results
Randomized controlled trials comparing P2Y12 inhibitor monotherapy after a short course of DAPT (≤3 months) vs. 12-month DAPT in ACS were included. The primary endpoint was major adverse cardiovascular events (MACE). All analyses included an interaction term for the P2Y12 inhibitor used as monotherapy. Trial sequential analyses were run to explore whether the effect estimate of each outcome may be affected by further studies. Seven trials encompassing 27 284 ACS patients were included. Compared with 12-month DAPT, P2Y12 inhibitor monotherapy after a short course of DAPT was associated with no difference in MACE [odds ratio (OR) 0.92, 95% confidence interval (CI) 0.76–1.12] and a significant reduction in net adverse clinical events (NACE) (OR 0.75; 95% CI 0.60–0.94), any bleeding (OR 0.54, 95% CI 0.43–0.66), and major bleeding (OR 0.47, 95% CI 0.37–0.60). Significant interactions for subgroup difference between ticagrelor and clopidogrel monotherapy were found for MACE (Pint = 0.016), all-cause death (Pint = 0.042), NACE (Pint = 0.018), and myocardial infarction (Pint = 0.028). Trial sequential analysis showed conclusive evidence of improved NACE with ticagrelor, but not with clopidogrel monotherapy, compared with standard DAPT.

Conclusions
In patients with ACS, P2Y12 inhibitor monotherapy after short DAPT halves bleeding without increasing ischaemic events compared with standard DAPT. Ticagrelor, but not clopidogrel monotherapy, reduced MACE, NACE, and mortality compared with standard DAPT, supporting its use after aspirin discontinuation.
Molecular Mechanisms of Temperature Tolerance Plasticity in an Arthropod
Authors: Aagaard Anne , Bechsgaard Jesper , Sørensen Jesper Givskov , Sandfeld Tobias , Settepani Virginia , Bird Tharina L , Lund Marie Braad , Malmos Kirsten Gade , Falck-Rasmussen Kasper , Darolti Iulia , Nielsen Kirstine Lykke , Johannsen Mogens , Vosegaard Thomas , Tregenza Tom , Verhoeven Koen J F , Mank Judith E , Schramm Andreas , Bilde Trine 
Published: July 2024

Abstract
How species thrive in a wide range of environments is a major focus of evolutionary biology. For many species, limited genetic diversity or gene flow among habitats means that phenotypic plasticity must play an important role in their capacity to tolerate environmental heterogeneity and to colonize new habitats. However, we have a limited understanding of the molecular components that govern plasticity in ecologically relevant phenotypes. We examined this hypothesis in a spider species (Stegodyphus dumicola) with extremely low species-wide genetic diversity that nevertheless occupies a broad range of thermal environments. We determined phenotypic responses to temperature stress in individuals from four climatic zones using common garden acclimation experiments to disentangle phenotypic plasticity from genetic adaptations. Simultaneously, we created data sets on multiple molecular modalities: the genome, the transcriptome, the methylome, the metabolome, and the bacterial microbiome to determine associations with phenotypic responses. Analyses of phenotypic and molecular associations reveal that acclimation responses in the transcriptome and metabolome correlate with patterns of phenotypic plasticity in temperature tolerance. Surprisingly, genes whose expression seemed to be involved in plasticity in temperature tolerance were generally highly methylated contradicting the idea that DNA methylation stabilizes gene expression. This suggests that the function of DNA methylation in invertebrates varies not only among species but also among genes. The bacterial microbiome was stable across the acclimation period; combined with our previous demonstrations that the microbiome is temporally stable in wild populations, this is convincing evidence that the microbiome does not facilitate plasticity in temperature tolerance. Our results suggest that population-specific variation in temperature tolerance among acclimation temperatures appears to result from the evolution of plasticity in mainly gene expression.
Small pelagic fish in the shallow Wadden Sea show opportunistic feeding with a strong benthic link
Authors: Maathuis Margot A M , Tulp Ingrid , Valk Sophie , van den Brink Xantia , Couperus Abraham S , Keur Marinus C , Nijland Reindert , Sakinan Serdar , van der Vorst Valerie , Poos Jan Jaap 
Published: July 2024

Abstract
Small pelagic fish (SPF) are crucial in marine food webs, transferring energy from plankton to higher trophic levels. This study focuses on herring (Clupea harengus) and sprat (Sprattus sprattus), addressing knowledge gaps in their feeding ecology in a nursery area, the Dutch Wadden Sea. We conducted a year-long, monthly survey, and used DNA metabarcoding to analyse zooplankton samples and stomach contents of two size classes of herring and sprat. Intra-, interspecific, and seasonal variations in fish condition, stomach fullness, and diet composition, along with selective feeding, were studied. Our study showed that condition and diet composition of herring and sprat, along with zooplankton density, exhibited a clear seasonal pattern. Juvenile herring and sprat displayed opportunistic feeding behaviour, rather than showing distinct prey selection. Besides copepods, we regularly observed (larvae of) benthic invertebrates in their diet. This emphasizes the crucial role of SPF as energy transfer agents, not solely between trophic levels, but also from benthic to pelagic habitats. Furthermore, fish post-larvae were part of the diet of larger herring (10–15 cm). Because of its unprecedented temporal and taxonomical detail, this study advances the understanding of seasonal dynamics of dominant components at the base of the Wadden Sea food web.
Challenging Stereotypes and Celebrating Family Bonds: Analysing the Representation of Older Adults in the Contemporary Chinese Dictionary
Authors: Tang Zhijie , Xu Hai 
Published: July 2024

Abstract
While there is growing interest in representations of older adults across media in general, specific studies of their representation in dictionaries are scarce. This study used content analysis, transitivity analysis and attitude system to explore how older adults’ identities are discursively constructed in the seventh edition of the Contemporary Chinese Dictionary (CCD7). On the negative side, CCD7 reveals several stereotypes (e.g., being frail and vulnerable), presenting old age as the antithesis of active youth. On the positive side, CCD7 uniquely highlights the significant role of older adults within the Chinese extended family structure. In addition, CCD7 emphasises that, in Chinese culture, caring for older adults is seen as a familial and social responsibility. Through the lens of CDA, this study contributes to our understanding of old age in lexicographic discourse and promotes inclusive language.
The Paroxysmal Depolarizing Shift
Authors: Prince David A. , Avoli Massimo 
Published: July 2024

Abstract
The mechanisms underlying the generation of interictal spikes identified in the electroencephalograms of epileptic patients and animal models of focal epilepsy have become more and more defined as technical advances in the analysis of these events have evolved. Central to this chapter, several investigators have focused on the paroxysmal depolarizing shift (PDS), which is thought to be the intracellular counterpart of the interictal spike generated by neuronal networks and intrinsic membrane conductances in both in vivo and in vitro preparations that mimic focal epileptic disorders. Here, we will review early in vivo experiments, in which the PDS was first identified, as well as later in vitro studies that were performed during GABAA receptor antagonism but also during concomitant enhancement of excitatory and inhibitory synaptic mechanisms. Finally, we will review the contribution of intrinsic neuronal mechanisms, and in particular dendritic Ca2+ action potentials, to the generation of the PDS. The findings reviewed here outline some concepts on brain function that have emerged by analyzing the generation of the PDS during the last six decades, and that may play a role in other pathological, and perhaps even physiological, activities.
Hippocampal Sclerosis in Temporal Lobe Epilepsy
Authors: Houser Carolyn R. 
Published: July 2024

Abstract
Hippocampal sclerosis (HS) is the most consistently observed histopathological finding in human temporal lobe epilepsy (TLE). Despite its long history, HS remains intriguing and continues to stimulate many questions about the functional significance of the histopathological alterations. Cell loss and gliosis have been hallmarks of HS since its earliest descriptions, and a classification system for subtypes of HS, based on the regions of predominant cell loss, was recently developed. These subtypes of HS are being studied in relation to clinical conditions and treatment planning, but the different patterns of histological changes could also inform studies of the basic mechanisms of TLE. While cell loss has been the focus of pathological studies of HS for many years, it has become increasingly important to consider the remaining neurons, as these are likely to be the sites of seizure initiation and propagation and thus the targets of treatment. Importantly, the major regions with remaining neurons (dentate gyrus, CA2, and the subiculum) all have unique morphological and functional changes that could influence epileptiform activity. Thus, the broad group of neuropathological changes in HS lead to numerous questions regarding their significance and functional effects, progressing from questions about the effects of different patterns of cell loss, to the influence of alterations in remaining neurons, and finally to consideration of the circuitry that could be established within the altered hippocampal formation. In this review, emphasis will be placed on studies of human HS, with inclusion of some related findings in animal models of epilepsy.
Mechanisms Leading to Initiation, Development, and Termination of Focal Seizures
Authors: de Curtis Marco , Suffczynski Piotr , Lévesque Maxime , Librizzi Laura , Uva Laura , Scalmani Paolo , Gnatkovsky Vadym , Avoli Massimo 
Published: July 2024

Abstract
The neurophysiological features of focal seizures have been extensively studied in humans and in animal models. Electroencephalogram (EEG), local field potentials, and cellular recordings have identified the prevalent characteristics of focal epileptic activities and highlighted the possible underlying mechanisms. In this chapter we will examine how focal seizures develop over time: (1) by describing EEG seizure patterns identified with intracerebral recordings in patients suffering from focal epilepsies during presurgical monitoring; (2) by reviewing the experimental findings obtained from animal models that reproduce the focal seizure patterns described in humans; and (3) by summarizing the most common hypotheses on the network mechanisms involved in the initiation, development, and termination of focal seizure activity. These findings suggest that regardless of the mechanisms involved in the onset of focal seizures, a quite reproducible sequence of excitability changes contribute to set the conditions for seizure progression and termination.
Cortical and Thalamic PV+ Interneuron Dysfunction in the Pathogenesis of Absence Epilepsy
Authors: Meyer Jochen , Maheshwari Atul 
Published: July 2024

Abstract
Childhood absence epilepsy is a common disorder causing recurrent unprovoked episodes of behavioral arrest associated with generalized spike-wave discharges on the electroencephalogram (EEG). The corticothalamic circuit that generates these discharges involves both excitatory neurons and parvalbumin-expressing inhibitory neurons (PV-INs) in both the cortex and thalamus. Corticothalamic PV-INs normally maintain fast feedforward inhibition (FFI), and dysfunction in FFI has been implicated in several drug-induced, monogenic mutant rodent and inbred rat models of absence epilepsy. This dysfunction causes a cascade of molecular events, resulting in the recruitment of increased tonic inhibition, and culminating in synchronous burst firing of the corticothalamic neurons mediated by T-type calcium channels. Recent studies using in vivo two-photon imaging and electrophysiology have shown that absence seizures are associated with reduced activity in most corticothalamic neurons, including PV-INs. Optogenetic and chemogenetic techniques have further revealed that reducing PV-IN activity within this circuit is sufficient to cause absence seizures. Further work to understand the role of PV-IN dysfunction in absence seizures is necessary since up to 30% of patients with absence seizures will not respond to first-line treatment with ethosuximide. Even when ethosuximide is effective, it does not specifically treat the PV-IN dysfunction, which may result in ongoing deficits in attention.
Pericytes and Microglia
Authors: Marchi Nicola , Brewster Amy L. 
Published: July 2024

Abstract
In seizure conditions, neuro-glio-vascular immune communications, blood–brain barrier (BBB) damage, and synaptic circuitry functional remodeling are dynamic processes that unfold over time and by brain region. These processes are associated with the generation and maintenance of epileptic networks. Accumulating evidence suggests that pericytes and microglial cells play critical roles in contributing to epileptogenic events, with a specific and renewed attention to pro- and anti-inflammatory equilibriums that strictly depend on the disease stage. Implications for pericytes include BBB dysfunction during and after seizures, while microglia is involved in cerebrovascular and neural network remodeling through altered surveillance, phagocytic, and inflammatory responses. These cellular modifications can span from the epileptogenic foci to seizure-propagating regions or networks. Understanding how pericyte and microglial cells interact with neuronal and cerebrovascular structures will facilitate the development of multitarget pharmacological strategies for epilepsy. Within this framework, the timing of pharmacological intervention could dictate therapeutic success, in the light of the varying and contrasting inflammatory and neurovascular trajectories that are cell-specific and unfold after a seizure or during epilepsy.
Progressive Myoclonus Epilepsy
Authors: Tegelberg Saara , Joensuu Tarja , Lehesjoki Anna-Elina 
Published: July 2024

Abstract
Unverricht-Lundborg disease (ULD; EPM1) is an inherited neurodegenerative disorder characterized by onset at 6–15 years, stimulus-sensitive, action-activated myoclonus, epilepsy, and progressive neurological deterioration. It is caused by biallelic pathogenic variants in the CSTB gene, encoding a cystatin B. The most common of these is an unstable expansion of a dodecamer repeat element in the promoter region of the gene, leading to marked downregulation of CSTB expression. Total loss of CSTB is associated with severe neonatal-onset encephalopathy. A cystatin B–deficient mouse models the EPM1 disease relatively well. Myoclonic seizures, preceded by microglial activation, develop at one month of age and are followed by progressive gray and white matter degeneration and motor problems. CSTB is an inhibitor of cysteine proteases of the cathepsin family showing both nuclear and cytoplasmic localization with partial co-localization with lysosomal markers. CSTB function has been linked to protecting neurons from oxidative damage through an oxidative stress-responsive cystatin B-cathepsin B signaling pathway. In the nucleus CSTB has been shown to participate in regulation of cell cycle, and histone H3 tail proteolytic cleavage. Downstream effects of CSTB dysfunction have also been implicated in apopotosis, microglial dysfunction, inflammation, neurogenesis and synapse physiology. Despite the progress made, the exact disease mechanisms in EPM1 remain elusive. This chapter discusses the clinical features of EPM1 and recent advances in understanding its pathophysiology.
Treating Lafora Disease with an Antibody-Enzyme Fusion
Authors: Gentry Matthew S. , Markussen Kia H. , Sun Ramon C. , Vander Kooi Craig W. 
Published: July 2024

Abstract
Lafora disease (LD) is a horrendous progressive myoclonic epilepsy that strikes healthy teenagers and leads to ever-worsening seizures with no relief from antiepileptic drugs; it then transitions to rapid dementia that ends in death typically after 10 years of onset. LD is the result of mutations in either the EPM2A or EPM2B/NHLRC1 gene that encodes the glycogen phosphatase laforin or the E3 ubiquitin ligase malin, respectively. A hallmark of LD is cytoplasmic, aberrant glycogen-like aggregates called Lafora bodies (LBs); thus, LD is also classified as a glycogen storage disease (GSD). Using LD mouse models, multiple laboratories definitively demonstrated that genetic reduction or elimination of glycogen synthesis decreased LB formation and rescued LD epilepsy, neurodegeneration, and brain inflammation. Thus, LBs are the etiological driver of LD. An antibody-enzyme fusion (AEF) was developed that ablates LBs and normalizes both cell signaling and brain metabolism. This AEF is a promising drug for the treatment of LD and other GSDs as well as a putative therapeutic platform for targeting other neurodegenerative diseases.
Heterogeneous Mechanisms of Spreading Depolarization and Seizures
Authors: Aiba Isamu 
Published: July 2024

Abstract
Spreading depolarization (SD) is a massive, slowly migrating wave of near-complete cellular depolarization of neurons and glia associated with profound cytotoxic edema. SD is frequently generated following acute brain injury and contributes to the transient and chronic deterioration of neurological conditions. Clinical and basic studies also suggest that SD is a significant contributing mechanism of headache and neurological deficits in some migraine with aura. Because of the increasing evidence supporting the role of SD in these clinical conditions, there is a growing interest in exploring other neurological disorders that involve SD, including epilepsy. Both basic and clinical studies repeatedly demonstrate that seizure and SD can be co-generated in a temporally and spatially associated manner, suggesting the possibility that SD may be a comorbid feature of epilepsy. On the other hand, some studies suggest that the chronically epileptic brain is resistant to SD, and thus the relationship is still unclear. For technical reasons, clinical evidence of spontaneous SD generation in epilepsy and its interaction with seizures is very limited. Because mechanisms of SD and seizures can vary significantly in different contexts, their potential interaction likely requires individual evaluation depending on the type of epilepsy. This chapter will review the similarity and distinctions of molecular and physiological mechanisms of seizures and SD, and then discuss their clinical interaction in different pathological settings.
New Models for Assessment of Antiseizure Activity
Authors: Metcalf Cameron S. , West Peter J. , Edwards Sharon F. , Wilcox Karen S. 
Published: July 2024

Abstract
Drug and therapy screening in models of epilepsy have made considerable advances in recent years. Rodent models of seizures are widely used in drug development and have helped to evaluate several approved antiseizure drugs (ASDs) over the last four decades. However, current ASDs are only fully effective in approximately two-thirds of patients, with the remaining populations experiencing drug-refractory seizures. Advances in understanding of additional model systems have provided new avenues for screening and evaluation of novel therapies in epilepsy. Zebrafish and Drosophila systems allow for high-throughput (vs. rodent assays) screening and drug repurposing studies and can be adapted for specific genetic populations. Similarly, mouse models based on genetic mutations corresponding to human pathology can be used and manipulated to study pathophysiology and screen novel compounds. Special populations of epilepsy, such as individuals developing seizures arising from central nervous system infection, can be modeled by viral-induced epilepsy models. The application of chemically induced seizures has been streamlined into moderate throughput assays in mice subjected to intra-amygdala or intra-hippocampal kainic acid, generating mice with repetitive seizures and other behavioral characteristics consistent with temporal lobe epilepsy. Finally, patient-derived induced pluripotent stem cells offer an opportunity to study patient-derived organoids, in the context of patient-specific genetic backgrounds, where drug screening can be used as a personalized medicine approach. These new approaches to drug development offer opportunities to complement and improve upon traditional screening approaches in rodents, in an effort to improve approaches to hard-to-treat epilepsy conditions.
Prophylaxis of Epileptogenesis in Injury and Genetic Epilepsy Models
Authors: Prince David A. , Gu Feng 
Published: July 2024

Abstract
The final common path for epileptogenesis involves pathological processes that enhance excitatory and/or decrease inhibitory synaptic transmission. In models involving traumatic- or status epilepticus–induced injury, both mechanisms underlie the epileptogenic process. Past results of the posttraumatic chronic neocortical isolation (UC) model suggested that limiting excessive excitatory connectivity with gabapentin and providing trophic support for defective GABAergic interneurons may serve as potential antiepileptogenic approaches following brain trauma. Results prompted further experiments to determine whether gabapentinoids and a small-molecule BDNF TrkB receptor partial agonist LM22A-4 (LM) would be effective in preventing seizures in posttraumatic epilepsy and genetic, noninjury epilepsy models with either enhanced excitatory synaptic connectivity (α2δ-1 overexpressing mice) or selective interneuronal abnormalities (Dravet syndrome [DS] mice with Scn1a mutation and loss of Nav1.1 predominantly in parvalbumin [PV] interneurons). Treatment of UC rats with LM mitigated structural and functional deficits of PV interneurons and suppressed epileptiform activity. Results from α2δ-1-overexpressing mice showed that treatment with pregabalin from P7 to P28 decreased excessive excitatory synaptogenesis and seizures consisting of aberrant electroencephalogram epileptiform activity associated with behavioral arrests, for at least 90 d after the end of treatment. Treatment of DS mice with LM from P13 to P19, before onset of seizures, improved PV interneuron function and inhibitory synaptic transmission, and decreased the incidence of seizures and mortality rate. Results show that antiepileptogenic approaches in injury models where epileptogenesis is multifactorial are also effective in genetic models with limited or single epileptogenic mechanisms.