bluuebunny/crossref_metadata_2025 huggingface dataset:
One dimensional lattice fluid mixture with nearest neighbour interactions
Authors: Yacine Sahnoun Ali , Djebbar Mustapha , Benmessabih Tounsi , Bakhti Benaoumeur
Published: July 2024

We present an exact derivation of the free energy functional of a fluid mixture of hard rods with arbitrary sizes on a one-dimensional lattice. Our approach is based on the Wertheim cluster theory which consists of mapping a system with finite range interactions to the system with pure hard-core interaction but with modified activities. We show that the free energy functional has the same form as the fundamental measure functional. The interactions part of the free energy has two contributions, one from the one-particle cavity restricted to the hard rod or hard-sphere diameter and a second from the two-particle cavity which includes the finite range of the interaction. In the limit of a one-component system, our results reduce to the one derived using the Markov chain approach. For vanishing interactions, the density functionals coincide exactly with the previously derived for the mixture of hard rods with pure hard-core interaction.
Development of high-performance fiber-reinforced concrete for drilling wellbore walls in highly mineralized strata and its sulfate attack resistanceattack resistance
Authors: Din Zongchuang , Yao Zhishu , Hu Kun , Fang Yu
Published: July 2024

Metakaolin has been incorporated into high-performance fiber-reinforced concrete for wellbore wall drilling to enhance its durability in strata with highly mineralized water. This study established a benchmark, utilizing fly ash, slag powder, and metakaolin as the factors in an orthogonal test to assess the durability of concrete against sulfate attack. The range analysis and an integrated balance method were employed to optimize the mix proportion, the optimized mix proportion of high-performance concrete was determined as concrete: cement: fly ash: slag powder: metakaolin: pumping agents: gravel: sand: water: polyvinyl alcohol = 1: 0.2: 0.075: 0.05: 0.106: 2.767: 1.556: 0.371: 0.003. The apparent and microscopic morphologies before and after the erosion of both the benchmark group and optimized mix proportion group were investigated. The triaxial permeability tests were conducted on these groups under varying confining pressures to elucidate concrete permeability trends. Additionally, a damage constitutive model for concrete under a sulfate attack was formulated based on the durability tests. This study could provide valuable insights into the industrial utilization of concrete in deep shafts within highly mineralized water strata in Northwestern China.
Simulation of tungsten impurity transport by DIVIMP under different divertor magnetic configurations on HL-3
Authors: ZHOU 周 Qingrui 庆瑞 , ZHANG 张 Yanjie 彦杰 , SANG 桑 Chaofeng 超峰 , LI 李 Jiaxian 佳鲜 , ZHENG 郑 Guoyao 国尧 , WANG 王 Yilin 艺霖 , WU 吴 Yihan 亦晗 , WANG 王 Dezhen 德真
Published: July 2024

Tungsten (W) accumulation in the core, depending on W generation and transport in the edge region, is a severe issue in fusion reactors. Compared to standard divertors (SDs), snowflake divertors (SFDs) can effectively suppress the heat flux, while the impact of magnetic configurations on W core accumulation remains unclear. In this study, the kinetic code DIVIMP combined with the SOLPS-ITER code is applied to investigate the effects of divertor magnetic configurations (SD versus SFD) on W accumulation during neon injection in HL-3. It is found that the W concentration in the core of the SFD is significantly higher than that of the SD with similar total W erosion flux. The reasons for this are: (1) W impurities in the core of the SFD mainly originate from the inner divertor, which has a short leg, and the source is close to the divertor entrance and upstream separatrix. Furthermore, the W ionization source (S
W0) is much stronger, especially near the divertor entrance. (2) The region overlap of S
W0 and

pointing upstream promote W accumulation in the core. Moreover, the influence of W source locations at the inner target on W transport in the SFD is investigated. Tungsten impurity in the core is mainly contributed by target erosion in the common flux region (CFR) away from the strike point. This is attributed to the fact that the W source at this location enhances the ionization source above the W ion stagnation point, which sequentially increases W penetration. Therefore, the suppression of far SOL inner target erosion can effectively prevent W impurities from accumulating in the core.
Exploring environmental condition of silvofishery pond to support the sustainability of mangrove management in Berau Regency, Indonesia
Authors: Mustafa Akhmad , Tarunamulia  , Ratnawati Erna , Paena Mudian , Kamariah  , Athirah Admi , Asaf Ruzkiah , Tahe Suwardi , Hendrajat Erfan Andi , Taukhid Imam , Asaad Andi Indra Jaya , Basir  , Ilman Muhammad
Published: July 2024

The integration of mangrove management with aquaculture, termed the silvofishery pond system, has been implemented in Berau Regency, East Kalimantan Province, Indonesia. A detailed survey was conducted to assess the features of mangrove terrain surrounding silvofishery ponds, aiming to enhance the productive and sustainable management of these mangrove areas in Berau Regency. This survey focused on various land characteristics such as topography, tidal patterns, water quality, soil properties, climate, and the state of mangrove vegetation. The health of mangrove vegetation was assessed by calculating the Important Value Index (IVI) across different growth stages: trees, saplings, and seedlings. The findings reveal that the mangrove adjacent to the silvofishery ponds in Berau Regency are home to 14 species from 13 genera and 10 families. Rhizophora mucronata displayed the highest IVI scores across all growth stages: 75.17% for trees, 93.14% for saplings, and 66.98% for seedlings, the latter shared with Rhizophora apiculata. Soil quality emerged as a critical limiting factor for land use in silvofishery ponds, particularly due to high potential acidity (low pH) and low nitrogen (N) content. To enhance soil quality, it is recommended that soil management practices such as remediation (via drying, submerging, flushing, or liming) and N supplementation through fertilization be employed. Furthermore, given the sparse mangrove vegetation density at the tree level (1,012 trees/ha), efforts to promote natural mangrove regeneration and prevent deforestation and degradation are advised. Considering the unique characteristics of the mangroves, the implementation of the komplangan model—a silvofishery approach that segregates mangroves restoration pond from grow-out ponds—is recommended to boost productivity and ensure sustainability in the coastal region of Berau.
Anomaly detection combining bidirectional gated recurrent unit and autoencoder in the context of e-commerce
Authors: Lin Yue
Published: July 2024

E-commerce platforms store a large amount of user personal information, transaction data, and financial information, which have extremely high value for hackers and criminals. Therefore, protecting the security of e-commerce platforms is particularly important, and intrusion detection is a technical means used to discover and respond to possible security threats and attacks. But with the development of Internet technology, there are more and more types of intrusion attacks and more sophisticated means. Traditional intrusion detection systems are difficult to cope with. This study proposes an anomaly detection model based on bidirectional gated loop units and autoencoders. The model learns HTTP text data, trains the model, and uses bidirectional gated loop units to convert text sequences from characters to numbers. The experimental results show that when the training set size is 1000, the false alarm rates of Analytic Hierarchy Process, Support Vector Machine, Long Short Term Recurrent Memory Network, and Improved end-to-end algorithm models are 0.30, 0.27, 0.23, and 0.10, respectively. The loss function values are 0.35, 0.28, 0.17, and 0.13, respectively. The F1 values are 0.78, 0.88, 0.91, and 0.99, and the accuracy rates are 0.88, 0.91, 0.95, and 0.99, respectively. The research results indicate that the proposed method model has excellent performance.
Underwater manipulator arm control based on Harris Hawk algorithm optimized RBF neural network
Authors: Zhao Chuanzhe , Wang Haibo , Song Yadi , Wang Ronglin , Li Zhifeng , Li Pengtao
Published: July 2024

This article addresses the control issues of underwater manipulator arms in complex marine environments, proposing a composite control strategy based on the Harris Hawk Optimization (HHO) algorithm and Radial Basis Function (RBF) neural network. Combining the global search capability of the HHO algorithm with the fast approximation characteristics of RBF neural networks, a self-adaptive control method for underwater manipulator arms is designed. By automatically optimizing the parameters of the neural network, the performance and robustness of the control system are enhanced. Through simulation experiments, the effectiveness of the proposed control algorithm is verified. The results show that compared with the traditional RBF neural network control and fuzzy sliding mode control, the optimized control algorithm proposed in this paper has significant improvement compared with both of them, demonstrates good control effect and high practical value, and provides an effective solution for the precise control of the underwater manipulator arm.
Characterization and electrochemical performance of plasma-nitrided titanium alloy for bipolar plates
Authors: Shen Hongyu , Wang Liang
Published: July 2024

Ti-N layer with a thickness about 1 ∼ 2.2 μm was formed on titanium alloys through plasma nitriding at 750 °C in NH3 and a mixture of NH3 and N2 (1:2) for 4 h. SEM and XRD were employed to characterize the microstructure and phase composition of nitrided layer. Electrochemical tests evaluated the anti-corrosion properties of the samples before and after nitrided in a simulated proton exchange membrane fuel cells (PEMFC) environment. Interface contact resistance (ICR) was also measured. Results indicated that the corrosion potential in cathodic conditions was increased from −415 mV for untreated titanium to 148 mV for that nitrided in mixture gas. While, the corrosion current density was reduced from 6.64 μA to 0.86 μA. Under a pressure of 140 N cm−2, the interfacial contact resistance of the untreated sample increased from 22.1 mΩ cm2 before corrosion testing to 40.5 mΩ cm2 after corrosion at cathodic conditions. The nitrided sample, on the other hand, saw its contact resistance rise from 4.5 mΩ cm2 before corrosion to 7.3 mΩ cm2 after corrosion. The Ti-N compound layer effectively diminished the corrosion current density and sustained an exceptionally low ICR under the simulated operating conditions of a bipolar plate.
High-bandwidth FPGA based randomized voltage states for controlling optoelectronic devices in QKD systems
Authors: Satija Aman , Cruise Dustin , Garg Vaibhav
Published: July 2024

We have developed an inexpensive system for generating random voltage states (RVS) on a FPGA platform. This system can be used for controlling optoelectronic devices in a quantum-key-distribution (QKD) system. We use an all-digital operation at the FPGA layer to generate two uncorrelated Boolean bit strings. These bit strings are converted to RVS using a multiplexer and a voltage buffer in order to drive commercially available optoelectronic devices. A National Instruments (N.I) real-time IO (RIO) platform was used for FPGA implementation. The FPGA layer was coupled to the desktop layer for real-time monitoring and logging of the Boolean bit strings. We characterize the performance of the multiplexer and the buffer and describe how their engineering performance trades-off with the fidelity of RVS generation.
The Institutional Foundations of Ukrainian Democracy
Authors: Kibita Nataliya
Published: July 2024

Ukraine and Russia are today at opposite ends of the political spectrum. Despite 300 years of full submersion into Russian authoritarian system, Ukraine has rejected authoritarianism. To explain why and how Ukraine’s road diverged from Russia’s, this monograph investigates the origins of regionalism in Ukraine, which is at the foundation of the Ukrainian institutional system. ‘Weak centre, strong regions’ was characteristic of both Ukraine and Russia in the early post-Soviet years. However, what was a detour for Russia was a long-standing framework in Ukraine. The story follows the relationship between Moscow, Kyiv, and the Ukrainian regions in the period from spring 1917 to summer 1994. Based on new archival material and guided by the theory of institutions, the book examines how interlinked political and economic incentives and constraints determined the opportunities and institutional interests of the Ukrainian leadership and the Ukrainian regions, and how the institutional framework affected the dynamic of the relationship between the central leadership in Moscow, the Ukrainian leadership, and the regions. It shows that, once established, the configuration of ‘weak centre, strong regions’ did not change, even when the Soviet centralized party-state system collapsed. The failure of the Ukrainian leadership to reconfigure the interplay of incentives and constraints that dictated the behaviour of the Ukrainian regions determined not only the insignificance of the disintegration of the Soviet system, but also the institutional weakness of the new Ukrainian executive branch and the failure by President Kravchuk to establish some form of authoritarian rule.
Bulygin on Legal Gaps and the Normativity of Law
Authors: Monti Ezequiel
Published: July 2024

This chapter reconstructs and examines Bulygin’s account of normative legal gaps. Bulygin argues for two main theses, namely, that it is possible for legal systems to have normative gaps thus understood (Possibility Thesis); and that when faced with normative gaps, judges have legal discretion (Discretion Thesis). The chapter grants the Possibility Thesis but argues against the Discretion Thesis. The chapter distinguishes between legal norms and the rights and obligations that obtain in virtue of them; and, correspondingly, between normative propositions and what the chapter calls genuinely normative propositions. These distinctions allow a distinction between normative gaps (in Bulygin’s sense) and what the chapter calls genuinely normative gaps. The chapter goes on to argue that Bulygin’s arguments establish the possibility of the former but not of the latter And if the latter are impossible, then judges have no legal discretion as a result of the former. The chapter concludes by showing that, even if they do not entail legal discretion, Bulygin’s notion of normative legal gaps is nevertheless significant.
Improved low-invasive mRNA electroporation method into immature mouse oocytes visualizes protein dynamics during development
Authors: Satouh Yuhkoh , Suzuki Emiko , Sasaki Keisuke , Sato Ken
Published: July 2024

One of the major causes of oocyte quality deterioration, chromosome segregation abnormalities manifest mainly during meiosis I, which occurs before and during ovulation. However, currently, there is a technical limitation in the introduction of mRNA into premature oocytes without impairing embryonic developmental ability. In this study, we established a low-invasive electroporation (EP) method to introduce mRNA into pre-ovulatory, germinal vesicle (GV) mouse oocytes in an easier manner than the traditional microinjection method. The EP method with an optimized impedance value resulted in the efficient introduction of mRNAs encoding enhanced green fluorescent protein (EGFP) into the GV oocytes surrounded by cumulus cells at a survival rate of 95.0%. Furthermore, the introduction of histone H2B-EGFP mRNA into the GV oocytes labeled most of the oocytes without affecting the blastocyst development rate, indicating the feasibility of the visualization of oocyte chromosomal dynamics that enable us to assay chromosomal integrity in oocyte maturation and cell count in embryonic development. The establishment of this EP method offers extensive assays to select pre-implantation embryos and enables the surveying of essential factors for mammalian oocyte quality determination.
Crucial role for sensory nerves and Na/H exchanger inhibition in dapagliflozin- and empagliflozin-induced arterial relaxation
Authors: Forrester Elizabeth A , Benítez-Angeles Miguel , Redford Kaitlyn E , Rosenbaum Tamara , Abbott Geoffrey W , Barrese Vincenzo , Dora Kim , Albert Anthony P , Dannesboe Johs , Salles-Crawley Isabelle , Jepps Thomas A , Greenwood Iain A
Published: July 2024

Aims

Sodium/glucose transporter 2 (SGLT2 or SLC5A2) inhibitors lower blood glucose and are also approved treatments for heart failure independent of raised glucose. Various studies have showed that SGLT2 inhibitors relax arteries, but the underlying mechanisms are poorly understood and responses variable across arterial beds. We speculated that SGLT2 inhibitor-mediated arterial relaxation is dependent upon calcitonin gene-related peptide (CGRP) released from sensory nerves independent of glucose transport.

Methods and results

The functional effects of SGLT1 and 2 inhibitors (mizagliflozin, dapagliflozin, and empagliflozin) and the sodium/hydrogen exchanger 1 (NHE1) blocker cariporide were determined on pre-contracted resistance arteries (mesenteric and cardiac septal arteries) as well as main renal conduit arteries from male Wistar rats using wire myography. SGLT2, CGRP, TRPV1, and NHE1 expression was determined by western blot and immunohistochemistry. Kv7.4/5/KCNE4 and TRPV1 currents were measured in the presence and absence of dapagliflozin and empagliflozin. All SGLT inhibitors (1–100 µM) and cariporide (30 µM) relaxed mesenteric arteries but had negligible effect on renal or septal arteries. Immunohistochemistry with TRPV1 and CGRP antibodies revealed a dense innervation of sensory nerves in mesenteric arteries that were absent in renal and septal arteries. Consistent with a greater sensory nerve component, the TRPV1 agonist capsaicin relaxed mesenteric arteries more effectively than renal or septal arteries. In mesenteric arteries, relaxations to dapagliflozin, empagliflozin, and cariporide were attenuated by the CGRP receptor antagonist BIBN-4096, depletion of sensory nerves with capsaicin, and blockade of TRPV1 or Kv7 channels. Neither dapagliflozin nor empagliflozin activated heterologously expressed TRPV1 channels or Kv7 channels directly. Sensory nerves also expressed NHE1 but not SGLT2 and cariporide pre-application as well as knockdown of NHE1 by translation stop morpholinos prevented the relaxant response to SGLT2 inhibitors.

Conclusion

SGLT2 inhibitors relax mesenteric arteries by promoting the release of CGRP from sensory nerves in a NHE1-dependent manner.
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

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

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

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

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

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

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

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

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

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

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

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

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

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

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.
Anti-inflammatory Strategies for Disease Modification
Authors: Vezzani Annamaria , Balosso Silvia , Varvel Nicholas H. , Dingledine Ray
Published: July 2024

Clinical and preclinical studies have confirmed that neuroinflammation is a salient feature of the epileptic brain. The engagement of several neuroinflammatory pathways has been documented after epileptogenic injuries and in the aftermath of ongoing seizure activity. Preclinical research over the past decade has demonstrated that the ensuing neuroinflammation after epileptogenic triggers promotes seizures, neuronal injury, blood–brain barrier dysfunction, and behavioral comorbidities. Thus, successful modulation of the neuroinflammatory cascade is a potential therapeutic strategy. An overarching goal of anti-inflammatory approaches is to quench pathogenic neuroinflammation while maintaining, or promoting, the homeostatic effects. In this chapter we focus on treatments that are close to clinical translation, outlining the experimental evidence supporting the use of the anti-inflammatory therapy for both reducing drug-resistant seizures and for providing disease-modification effects. Approaches targeting IL-1β-IL-1R1 signaling, COX-2 pathways, immune-endothelial cell interations, statins, and dexamethasone are discussed. Recent combinatorial approaches with disease-modifying effects are highlighted. Successful development of anti-inflammatory therapies for epilepsy faces hurdles. The timing of therapeutic administration after epileptogenic triggers should, ideally, preserve the physiological roles of inflammation while opposing pathological ones. Biomarkers and consideration of epilepsy etiology can help identify patients who will best benefit from anti-inflammatory drugs. Clinical studies of anti-inflammatory treatments are underway in patients with drug-resistant seizures, and the results are described here. New clinical trial designs are likely needed to take into account the differences in mechanism of action between anti-inflammatory and conventional antiseizure medications.
Cell Therapy for Treatment of Epilepsy
Authors: Bröer Sonja , Vogt Daniel
Published: July 2024

Cell transplantation could offer a strategy to overcome pharmacoresistance in epilepsy if transplanted cells can survive long term within the host brain, migrate into appropriate brain regions, differentiate into interneurons (INs) that increase inhibitory tone within the epileptic network, and integrate into the circuitry by forming synapses with host neurons. Several studies have demonstrated all of the above-mentioned prerequisites of a successful IN transplantation using rodent INs derived from the medial ganglionic eminence (MGE). They showed that INs are effective in decreasing seizure frequency consistently and in the long term across a variety of animal models. Behavioral comorbidities of epilepsy could be alleviated, and even hippocampal neuropathology of the disease was reduced. While use of rodent INs is feasible for preclinical research, a human cell product is needed for clinical translation. Protocols for IN in vitro differentiation from human pluripotent stem cells (PSCs) have been developed. First, data from transplantation studies in models of epilepsy confirm the promising disease-modifying activity that was observed with rodent MGE-derived INs: human IN transplantation was effective in reducing seizure burden, while no obvious adverse effects were associated with it. Further research on characterization of cells prior to transplant, process improvements, and good manufacturing practice production will be needed to ensure safety of an IN cell product; however, the recent advances in our ability to generate MGE-like cells from PSCs, in-depth characterization of cells with modern techniques and the combinatorial use of electrophysiology, optogenetics, and translational immunodeficient animal models to evaluate disease-modifying activity have brought human IN transplantation significantly closer to clinical application.
Mechanisms of Ketogenic Diet Action
Authors: Williams Robin S. B. , Boison Detlev , Masino Susan A. , Rho Jong M.
Published: July 2024

At the turn of the first century of ketogenic diet (KD) use for medically intractable epilepsy, investigators have uncovered a multiplicity of potential mechanisms that may underlie the clinical effects of this metabolism-based treatment. In the process, there have emerged important insights into the biochemical and metabolic bases of epilepsy, and novel approaches and targets that can be exploited for experimental and clinical therapeutics. Historically, metabolic changes thought to mediate the KD’s antiseizure effects have included—but are not limited to—ketosis, glycolytic restriction, increased purinergic and GABAergic neurotransmission, fatty acid modulation of ion channels, improved cellular and mitochondrial bioenergetics, and a reduction in oxidative stress. More recently, it has been shown that the KD and its variants, such as the medium-chain triglyceride diet, may induce anti-inflammatory, neuroprotective, epigenetic, and even antiepileptogenic effects. Finally, the gut microbiome has been linked to enhanced central inhibitory-excitatory balance through changes in the blood metabolome. As dietary treatments have been increasingly shown to evoke a wide array of metabolic, physiologic, and hormonal effects, future research will undoubtedly reveal an even more complex mechanistic framework for KD action, but one which should enable the development of improved dietary formulations, or simplified treatments based on the biology of specific biochemical substrates and enzymes, not only for epilepsy but also potentially for a broader range of neurological disorders.