bluuebunny/crossref_metadata_2025_split huggingface dataset:
Connexins, Pannexins, and Epilepsy
Authors: Zhang Liang , Zoidl Georg R. , Carlen Peter L. 
Published: July 2024

Abstract
Connexins are proteins that form gap junctions which “connect” cells together, permitting the passage of small molecules and electricity. Since epilepsy is thought of as a disease of neuronal hypersynchrony, it is natural to consider these molecules with the gap junctions they form as playing a significant role in epilepsy. Over time, the “connections” of connexins to epilepsy are becoming more complicated and deeper. Adding to the complexity was the discovery of a family of membrane channels, the pannexins, which were initially mistaken for a second family of gap junction forming proteins. However, they, too, clearly play a major role in epilepsy. Herein we start with an introduction to the complex biology of both protein classes, followed by discussions of their multiple roles in epilepsy. These include such phenomena as direct intercellular communication between neurons and more recently, between glia, now increasingly recognized as key players in epilepsy. Also, the functions of membrane channels formed by connexins (hemichannels) and pannexins in promoting seizure activity and pathological consequences are discussed.
Transition to Seizure from Cellular, Network, and Dynamical Perspectives
Authors: Chang Wei-Chih , Kudlacek Jan , Jiruska Premysl , Jefferys John G. R. 
Published: July 2024

Abstract
The cellular and network mechanisms of seizure emergence (ictogenesis) remain unknown. Recent studies brought new fundamental insights about the complex nature of seizure genesis and the dynamical principles that govern the shift of epileptic networks dynamics into the seizure state. In this chapter, we describe new perspectives on how to approach understanding ictogenesis. Primarily, we focus on the latest data about the dynamical pathways and pathophysiological processes that drive the transition to seizure. In addition, we review recent evidence about the existence of long-term fluctuations in seizure likelihood which represent a missing piece in the mosaic of ictogenesis. We demonstrate that combining the cellular and network mechanisms at multiple temporal scales (ranging from epileptogenesis to seizure initiation) is a crucial step to a unified theory of seizure genesis.
Optogenetic Modulation of Focal Seizures
Authors: Lévesque Maxime , Avoli Massimo , Kokaia Merab 
Published: July 2024

Abstract
Optogenetics rests on the activation of light-gated ion channels or pumps in transgenic animals, and it is used to reversibly excite or silence specific neuronal populations, with millisecond precision and with a higher spatial accuracy than electrical stimulation. To date, epilepsy researchers have used optogenetics to study this neurological disorder, and in particular focal seizures that originate from a discrete brain area as in mesial temporal lobe epilepsy. Here, we will review findings obtained by employing optogenetics in in vitro and in vivo models of focal epileptiform synchronization. We will also address the use of this technique to control acute and chronic spontaneous seizures induced by the administration of chemoconvulsants in animal models of mesial temporal lobe epilepsy, such as the kainic acid and the pilocarpine model. These findings reveal that optogenetic activation or inhibition of excitatory or inhibitory cells can exert paradoxical effects on seizure occurrence depending on the frequency and timing of light stimulation, as well as on the targeted neuronal populations. We also consider the limitations associated with the use of optogenetics and the potential issues that must be solved before this approach is translated to human application. We conclude that optogenetics, despite some limitations, represents an innovative and promising approach to improve our understanding of brain function in health and disease.
Balancing Seizure Control with Cognitive Side Effects Using Changes in Theta
Authors: Toprani Sheela , Gurkoff Gene G. , Shahlaie Kiarash , Girgis Fady , Saez Ignacio , Kennedy Jeffrey , Moxon Karen A. 
Published: July 2024

Abstract
This chapter discusses the growing evidence that seizure generation and cognitive deficits have a similar pathological source characterized by, but not limited to, deficits in theta oscillations and their influence on interneurons that is part of a larger pathological brain network. The authors discuss new tools and techniques that are being used to identify this larger pathological network, how it overlaps with cognitive networks, and how therapies need to be developed that consider both the seizure network and the overlap with cognitive networks. A new framework is presented that describes oscillatory states in epilepsy as alternating between hyper- and hyposynchrony rather than solely the spontaneous transition to hyperexcitability characterized by the seizures. This framework suggests a pathological imbalance between excitation and inhibition in favor of synchronous inhibition during interictal theta oscillations that could account for both the seemingly spontaneous nature of seizures and comorbid cognitive deficits. The chapter concludes that there is a need to understand epilepsy as impacting extensive brain networks in order to optimize outcome for patients.
Role of Ion Concentration Dynamics in Epileptic Seizures
Authors: González Oscar C. , Timofeev Igor , Bazhenov Maxim 
Published: July 2024

Abstract
The regulation of transmembrane ion flux is crucial for maintaining physiological neuronal activity and preventing the occurrence of epileptic seizures. The net effect (e.g., depolarization or hyperpolarization) of the transmembrane ion flux is determined by the relative ion concentration gradients established across the cellular membrane. Because of the tight regulation of neuronal excitability and dynamics by changes in the ion concentrations, the brain has evolved multiple mechanisms to precisely regulate and maintain these concentration gradients. It has been demonstrated that the breakdown in the maintenance of ion gradients may lead to development of seizure discharges and may underly various forms of pathological neuronal activity. It is now well established that during a seizure discharge, the extracellular potassium concentration substantially increases, while the concentrations of extracellular sodium and calcium decrease. More recently, experimental recordings and computational models have demonstrated preictal increases in the intracellular chloride concentration in pyramidal neurons. This chapter discusses the effects of the ion concentration dynamics on seizure initiation, progression, and termination with the goal of providing novel insights into the underlying biophysical mechanisms of epileptic seizures.
Computational EEG Analysis of Human Epileptogenic Networks
Authors: Gnatkovsky Vadym , Schindler Kaspar 
Published: July 2024

Abstract
With the modern development of electroencephalogram (EEG) recording technology (stereo-EEG, grid, strip, and microelectrodes), computational EEG analysis started to play an essential role in assisting traditional visual EEG evaluation. The number of recording electrodes and the temporal resolution of these modern recording technologies are far beyond the human capability to rapidly extract and integrate all necessary information for studies of epileptogenic networks. This chapter describes the state of the art of computational EEG analysis. It reviews and discusses different computational approaches and achievements in the approximation of the epileptogenic zone, in seizure pattern recognition, seizure classification, and in the understanding of seizure generation mechanisms.
Clinical Features and Molecular Mechanisms Underlying Autoantibody-Mediated Seizures
Authors: Mathy Alexandre , Irani Sarosh R. 
Published: July 2024

Abstract
The last two decades have seen the discovery of a plethora of cell-surface autoantibodies causally implicated in clinically distinctive central nervous system (CNS) diseases. These autoantibody-mediated neurological disorders frequently present with multifocal neurological and psychiatric symptoms with both focal and generalized seizures as a core feature. This chapter describes the clinical spectrum of autoantibody-mediated CNS disorders, focusing on autoantibodies which target the extracellular domains of cell-surface antigens, including NMDAR and LGI1. In addition, the preclinical immune mechanisms underlying the genesis and propagation of these conditions are explored, and the chapter reviews how these autoantibodies directly modulate neuronal and circuit functions to explain the observed clinical features.
Epigenetics
Authors: Kobow Katja , Khan Nadia 
Published: July 2024

Abstract
Epigenetics refers to those mechanisms that allow a transient stimulus to induce long-lived programs of gene expression changes without altering the underlying DNA sequence itself. Epigenetic regulators function by catalyzing the modification of DNA or histone protein tails, which, in turn, up- or down-regulate the transcription of target genes. Originally thought to be static in terminally differentiated cells, it is now known that epigenetic processes are active and dynamic in mature neurons. Their function or perturbation may be sufficient to develop common neurological disorders such as epilepsy. This chapter provides a critical overview of key epigenetic changes detected in human patients and experimental epilepsy models. The chapter reflects on how these data impact epileptogenesis, what role epigenetic mechanisms may play in facilitating disease pathogenesis, and how it influences the chronic epileptic state. In the end, the chapter briefly discusses the potential for targeting epigenetic modulators as a new source of therapeutic intervention in epilepsy.
Machine-Learning Approach to Discover Novel Biomarkers for Posttraumatic Epilepsy
Authors: Ciszek Robert , Manninen Eppu , Gröhn Olli , Tohka Jussi , Pitkänen Asla 
Published: July 2024

Abstract
In this chapter, machine learning was applied to detect traumatic brain injury (TBI), posttraumatic epilepsy (PTE), and severity of PTE in a rat TBI model using data from animal weight, parameters related to TBI induction, multiple behavioral tests, and cortical lesion volumes calculated from magnetic resonance imaging (MRI). The combined data from all assays allowed perfect separation of naïve and sham-operated control animals from TBI animals. However, PTE was only detectable when the threshold for PTE was set at three or more observed seizures. These results imply that less severe forms of PTE were poorly reflected on the assays used.
Human Epilepsy Gene Discovery
Authors: Bonkowski Emily S. , Mefford Heather C. 
Published: July 2024

Abstract
The application of genome-wide technologies has accelerated the discovery of genetic and genomic etiologies for the epilepsies. Gene discovery has been most successful in the developmental and epileptic encephalopathies, and genetic testing is now routinely implemented in the clinical setting. Yet a significant percentage of affected individuals remain undiagnosed, and identifying the genetic underpinnings of generalized and focal epilepsies has lagged. Emerging technologies and analysis approaches offer promise for continued discovery of disease-associated variation. Examples include long-read sequencing, genome-wide methylation studies, and development and application of polygenic risk estimates.
Functional Exploration of Epilepsy Genes in Patient-Derived Cells
Authors: Varela Maria C. , Samarasinghe Ranmal , Parent Jack M. 
Published: July 2024

Abstract
Advances in human induced pluripotent stem cell (iPSC) approaches have greatly expanded the use of patient-derived cellular models, including cortical-like neurons and brain organoids, to study genetic epilepsies. New protocols to differentiate iPSCs into various neural cell types, and to generate brain region-specific organoids, have accelerated progress. In addition, the application of gene editing techniques adds rigor to these studies and offers the opportunity to model rare genetic epilepsies by enabling correction or insertion of mutations to generate isogenic controls or virtual patients, respectively. Studies using patient-derived cells have provided insight into the mechanisms underlying seizures and associated comorbidities for an increasing number of epilepsy gene variants. In this chapter, methods for generating iPSCs, the culture and gene editing of human pluripotent stem cells (hPSCs; both iPSCs and human embryonic stem cells), and differentiation strategies to derive cortical-like neurons are described. Next, physiological assays that can be applied to study hPSC-derived neuronal and network activity are discussed. Finally, the chapter reviews studies interrogating the functional effects of specific epilepsy gene variants using hPSC-derived 2D neural and 3D brain organoid cultures, as well as the use of iPSC-derived cardiac myocytes to study the most devastating epilepsy complication, sudden unexpected death in epilepsy (SUDEP).The chapter ends with a description of current challenges and future directions for hPSC modeling of genetic epilepsies.
The Neuronal Ceroid Lipofuscinoses
Authors: Mole Sara E. 
Published: July 2024

Abstract
The neuronal ceroid lipofuscinoses (NCL), also known as Batten disease, are a group of inherited lysosomal storage disorders that share similar pathological and clinical features. They are characterized by accumulation of autofluorescent storage material within the lysosome and the death of neurons. Clinical presentation includes medically refractory epilepsy, visual failure, and motor and cognitive decline, usually beginning in childhood and ending in premature death. Each NCL is caused by mutations in a single gene and is associated with a typical age of onset and disease progression. However, all NCL also have a broader age of onset and disease course. Considerable expertise has been developed in the care and management of patients. There is one treatment in the clinic and others are in development.
Artificial Intelligence–Guided Behavioral Phenotyping in Epilepsy
Authors: Gschwind Tilo , Soltesz Ivan 
Published: July 2024

Abstract
A major impediment to progress in basic epilepsy research is the fact that evidence-based, rigorous translational research is not only prohibitively time and labor-intensive, such as 24/7 video-electroencephalogram recordings, but rests on inherently subjective scoring by human observers, as exemplified by the Racine scale. Recent technical progress in machine learning and computer vision highlighted a variety of novel possibilities for quantifying behavior in animal models of epilepsies. This chapter briefly reviews the latest advances in artificial intelligence (AI)-guided animal motion tracking and segmentation of pose dynamics that bear great potential of revolutionizing behavioral phenotyping in basic epilepsy research. As an emerging field fueled by the recent successes of deep learning, AI-guided behavioral phenotyping will be discussed primarily in order to provide insights into the fundamentals of the field and at the same time raise awareness of potential pitfalls of the underlying technology. By concisely surveying the diverse and rapidly growing landscape of the relevant methods and toolboxes available in neuroscience research, this chapter aims to spark interest in AI-aided behavioral phenotyping in the epilepsy community.
Disease Biology Factors Accounting for Epilepsy Severity
Authors: Dedeurwaerdere Stefanie , Marra Vincenzo , Johnson Michael R. 
Published: July 2024

Abstract
Over the last decade substantial progress has been made in understanding the genetic contributions to epilepsy. While targeted treatments for monogenic epilepsies are starting to emerge, the substantial heterogeneity of epilepsy poses a challenge to the development of broadly useful therapeutics for the refractory complex genetic epilepsies as well as acquired forms of the disease. The next frontier will be to increase our understanding of convergent epilepsy pathways so as to discover novel and broadly applicable disease-modifying therapies. This chapter posits a unifying conceptual framework for epilepsy for identifying convergent mechanisms across diverse genetic and acquired epilepsies. It is framed in earlier work around the nature of drug-resistant epilepsy which points to an inherent epilepsy severity rather than in the traditional pharmacological considerations external to the development and maintenance of the disease itself. This chapter aims to develop the intrinsic severity hypothesis beyond the nature of the epileptic perturbation and consider its cellular and molecular context more broadly. Specifically, the chapter reconceptualizes drug refractory epilepsy as a failure of homeostatic mechanisms to maintain the set point of the brain within boundaries responsive to standard antiseizure medication within the context of heterogeneous epileptogenic substrates. This framework offers a potential new insight both into the classification of an individual’s epilepsy and innovative therapeutic strategies that go beyond merely targeting the ictal substrate.
Epileptogenic Channelopathies Guide Design of NBI-921352, a Highly Isoform-Selective Inhibitor of NaV1.6
Authors: Johnson J. P. , Cutts Alison J. , Empfield James R. , Cohen Charles J. 
Published: July 2024

Abstract
NBI-921352 is the first highly isoform selective inhibitor of NaV1.6 voltage-gated sodium channels (NaVs) to enter clinical development for epilepsy. Nonselective inhibitors of NaVs have long been a mainstay of epilepsy pharmacotherapy. Many such NaV inhibitors are available, but they are not mechanistically well differentiated. They all inhibit via the same highly conserved binding site, and they inhibit the distinct NaV isoforms equivalently. This broad NaV inhibition limits the utility of these drugs, as dose levels required to reduce seizures can cause tolerability issues in both the central nervous and cardiovascular systems. The rationale to develop NBI-921352 was to take a precision medicine approach to developing novel NaV inhibitors. This approach has been validated preclinically, both in scn8a gain-of-function mutant cell lines and in Scn8a gain-of-function mice. NBI-921352 should improve tolerability by stripping away effects mediated by inhibition of the NaVs of cardiac cells (NaV1.5), muscle cells (NaV1.4), and inhibitory interneurons (NaV1.1). Despite the selective nature of NBI-921352, the compound retains the ability to reduce neural excitability and increases seizure resistance in rodents. NBI-921352 is currently entering clinical trials to establish whether the improved properties observed in rodents translate to human epilepsy patients
A tight N/O–potential relation in star-forming galaxies
Authors: Boardman N , Wild V , Asari N Vale 
Published: July 2024

ABSTRACT
We report a significantly tighter trend between gaseous N/O and $M_*/R_\mathrm{ e}$ (a proxy for gravitational potential) than has previously been reported between gaseous metallicity and $M_*/R_\mathrm{ e}$, for star-forming galaxies in the Mapping Nearby Galaxies at Apache Point Observatory (MaNGA) survey. We argue this result to be a consequence of deeper potential wells conferring greater resistance to metal outflows while also being associated with earlier star-formation histories, combined with N/O being comparatively unaffected by metal-poor inflows. The potential–N/O relation thus appears to be both more resistant to short time-scale baryonic processes and also more reflective of a galaxy’s chemical evolution state, when compared to previously considered relations.
Ethical Dimensions of Population-Based Lung Cancer Screening in Canada: Key Informant Qualitative Description Study
Authors: Pahwa Manisha , Abelson Julia , Demers Paul A , Schwartz Lisa , Shen Katrina , Vanstone Meredith 
Published: July 2024

Abstract
Normative issues associated with the design and implementation of population-based lung cancer screening policies are underexamined. This study was an exposition of the ethical justification for screening and potential ethical issues and their solutions in Canadian jurisdictions. A qualitative description study was conducted. Key informants, defined as policymakers, scientists and clinicians who develop and implement lung cancer screening policies in Canada, were purposively sampled and interviewed using a semi-structured guide informed by population-based disease screening principles and ethical issues in cancer screening. Interview data were analyzed using qualitative content analysis. Fifteen key informants from seven provinces were interviewed. Virtually all justified screening by beneficence, describing that population benefits outweigh individual harms if high-risk people are screened in organized programs according to disease screening principles. Equity of screening access, stigma and lung cancer primary prevention were other ethical issues identified. Key informants prioritized beneficence over concerns for group-level justice issues when making decisions about whether to implement screening policies. This prioritization, though slight, may impede the implementation of screening policies in a way that effectively addresses justice issues, a goal likely to require justice theory and critical interpretation of disease screening principles.
A sucrose-binding protein and β-conglycinins regulate soybean seed protein content and control multiple seed traits
Authors: Lakhssassi Naoufal , El Baze Abdelhalim , Knizia Dounya , Salhi Yasser , Embaby Mohamed G , Anil Erdem , Mallory Cullen , Lakhssassi Aicha , Meksem Jonas , Shi Haiying , Vuong Tri D , Meksem Kenza , Kassem My Abdelmajid , AbuGhazaleh Amer , Nguyen Henry T , Bellaloui Nacer , Boualem Adnane , Meksem Khalid 
Published: July 2024

Abstract
Expanded agriculture production is required to support the world's population but can impose substantial environmental and climate change costs, particularly with intensifying animal production and protein demand. Shifting from an animal- to a plant-based protein diet has numerous health benefits. Soybean (Glycine max [L.] Merr.) is a major source of protein for human food and animal feed; improved soybean protein content and amino acid composition could provide high-quality soymeal for animal feed, healthier human foods, and a reduced carbon footprint. Nonetheless, during the soybean genome evolution, a balance was established between the amount of seed protein, oil, and carbohydrate content, burdening the development of soybean cultivars with high proteins (HPs). We isolated 2 high-seed protein soybean mutants, HP1 and HP2, with improved seed amino acid composition and stachyose content, pointing to their involvement in controlling seed rebalancing phenomenon. HP1 encodes β-conglycinin (GmCG-1) and HP2 encodes sucrose-binding protein (GmSBP-1), which are both highly expressed in soybean seeds. Mutations in GmSBP-1, GmCG-1, and the paralog GmCG-2 resulted in increased protein levels, confirming their role as general regulators of seed protein content, amino acid seed composition, and seed vigor. Biodiversity analysis of GmCG and GmSBP across 108 soybean accessions revealed haplotypes correlated with protein and seed carbohydrate content. Furthermore, our data revealed an unprecedented role of GmCG and GmSBP proteins in improving seed vigor, crude protein, and amino acid digestibility. Since GmSBP and GmCG are present in most seed plants analyzed, these genes could be targeted to improve multiple seed traits.