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Bidirectional control of generalized absence epilepsy networks via real-time direct depolarization of thalamocortical neurons
Get PDFAbsence seizures (ASs), characterized by bilateral spike-and-wave discharges (SWDs), are a hallmark of idiopathic generalized epilepsies. We investigated the role of thalamocortical (TC) neurons in the generation and termination of ASs using optogenetic techniques in freely behaving GAERS rats, a well-established AS model. We demonstrate that direct depolarization of ChR2-transfected TC neurons in the ventrobasal thalamic nuclei during quiet wakefulness (QW) reliably elicits ethosuximide-sensitive ASs that have similar duration and frequency to those of spontaneous ASs, while showing little and no effect during active wakefulness (AW) and slow wave sleep (SWS), respectively. Light-stimulation of TC neurons fails to elicit ASs during AW, QW and SWS in non-epileptic control (NEC) rats, whereas it could evoke short ASs in Wistar rats, prevalently during QW. Notably, brief light stimulation effectively halted ongoing spontaneous ASs in GAERS rats (i.e. both SWDs and immobility), immediately altering thalamic multi-unit activity from rhythmic to irregular firing, irrespective of the SWD phase at which it was delivered. These findings support the view that the excitability of cortico-thalamic-cortical network is highly behavioural state-dependent, with increased susceptibility to the induction of ASs during QW, thus questioning the necessity of low-threshold burst firing of TC neurons in the generation of these seizures. Moreover, they highlight the dual control of ASs by TC neurons, underscoring their potential as therapeutic targets for AS modulation. Copyright © 2025 The Author(s). Published by Elsevier Ltd.. All rights reserved
Optimal power settings have major impact on procedural efficiency in pulmonary vein isolation guided by robotic magnetic navigation
Get PDFDecoupling Behavioral Domains via Kynurenic Acid Analog Optimization: Implications for Schizophrenia and Parkinson’s Disease Therapeutics
Get PDFKynurenic acid (KYNA), a putative neuroprotective agent, modulates glutamatergic pathways in schizophrenia and Parkinson’s disease but is limited by acute motor activity impairments (e.g., ataxia). Research leveraging animal disease models explores its structure–activity relationship to enhance therapeutic efficacy while mitigating adverse effects, addressing global neuropsychiatric disorders affecting over 1 billion people. Structural analogs of KYNA (SZR-72, SZR-73, and SZR-81) were designed to uncouple therapeutic benefits from motor toxicity; yet, systematic comparisons of their acute behavioral profiles remain unexplored. Here, we assess the motor safety, time-dependent effects, and therapeutic potential of these analogs in mice. Using acute intracerebroventricular dosing, we evaluated motor coordination (rotarod), locomotor activity (open-field), and stereotypic behaviors. KYNA induced significant ataxia and stereotypic behaviors at 15 min, resolving by 45 min. In contrast, all analogs avoided acute motor deficits, with SZR-73 maintaining baseline rotarod performance and eliciting a delayed decrease in ambulation and inquisitiveness in open-field assays. These findings demonstrate that the structural optimization of KYNA successfully mitigates motor toxicity while retaining neuromodulatory activity. Here, we show that SZR-73 emerges as a lead candidate, combining transient therapeutic effects with preserved motor coordination. This study advances the development of safer neuroactive compounds, bridging a critical gap between preclinical innovation and clinical translation. Future work must validate chronic efficacy, disease relevance, and mechanistic targets to harness the full potential of KYNA analogs in treating complex neuropsychiatric disorders
Can Ukrainians Claim Compensation for War Damage under the Russia-Ukraine BIT? An International Investment Law Experiment
Get PDFAutomation in action: Experience with quick and cost-efficient administrative decisions in Hungary
Get PDFAutomated decision-making can streamline administrative procedures, reducing the burden on authorities in straightforward cases. However, a concerning trend emerges: negative decisions challenged by clients are often so simplified that they render judicialreview meaningless, leaving issues unresolved. This is not merely a technical issue but a constitutional one. Clients are frequently deprived of meaningful reasoning, procedural safeguards, and effective legal remedies. Administrative decisions should uphold legality and transparency, ensuring fair proceedings. When a decision lacks proper justification and courts cannot assess its legality, it becomes unsuitable for review, undermining due process. If automation leads to decisions lacking transparency and accountability, it threatens fundamental legal principles.This study aims to show how automated -decision making is done in practice and what legal problems has emerged already by exploring casefiles and judicial decisions to highlight the risks of automated decision-making and calls for a balanced approach to maintain efficiency while safeguarding constitutional rights and judicial oversight
Percutaneous Superficial Temporal Artery Access Facilitating Carotid Artery Stenting Performed From Distal Radial Artery
Get PDFFirst-Year Teacher Education Students’ Epistemological Beliefs About Science and History: Domain-Specific Profiles and Relationships
Get PDFThis study investigates the developmental levels of epistemological beliefs (EBs) about science and history among first-year teacher trainees ( n = 146) through domain-specific questionnaires. A between-person analysis was used to examine the effect of academic studies and gender differences. Further, we employed a person-centred approach, k-means cluster analysis, to identify EB profiles for both domains. The results show that the impact of academic studies is greater on discipline-specific epistemological beliefs in history than in science, while the effect of gender is not significant in either area. We identified three EB profiles for both domains and found a significant positive correlation between the domain-specific EB profiles. A quarter of student teachers have a sophisticated profile in both science and history. Our research confirms the approach that individuals’ domain-specific epistemological beliefs develop in relation to domain-general beliefs. The results, in addition to contributing to a better understanding of the development of epistemological beliefs, also carry important implications for teacher education
