A Chemo-Enzymatic Cascade Strategy for the Synthesis of Phosphatidylcholine Incorporated with Structurally Diverse FAHFAs.

Fatty acid esters of hydroxy fatty acids (FAHFAs), a newly discovered class of human endogenous complex lipids showing great promise for treating diabetes and inflammatory diseases, exist naturally in extremely low concentrations. This work reports a chemo-enzymatic approach for the comprehensive synthesis of phospholipids containing FAHFAs via sequential steps: hydratase-catalyzed hydration of unsaturated fatty acids to generate structurally diverse hydroxy fatty acids (HFAs), followed by the selective esterification of these HFAs with fatty acids mediated by secondary alcohol-specific Candida antarctica lipase A (CALA), resulting in the formation of a series of diverse FAHFA analogs. The final synthesis is completed through carbodiimide-based coupling of FAHFAs with glycerophosphatidylcholine. Optimal reaction conditions are identified for each step, and the substrate affinity of CALA, responsible for the catalytic mechanisms during FAHFA production, is evaluated through molecular docking. Compared to multistep lab-tedious chemical synthesis, this route, relying on natural building blocks and natural biocatalysts, is significantly facile, scalable, and highly selective, affording high yields (74-98 mol %) in each step for the construction of higher FAHFA-PC series (10/12/13-FAHFAs). The developed strategy aims to increase the availability of naturally occurring FAHFA species and provide the tools for the construction of versatile and novel analogs of FAHFA conjugates.

Characteristic Changes of the Stance-Phase Plantar Pressure Curve When Walking Uphill and Downhill: Cross-Sectional Study.

BACKGROUND: Monitoring of gait patterns by insoles is popular to study behavior and activity in the daily life of people and throughout the rehabilitation process of patients. Live data analyses may improve personalized prevention and treatment regimens, as well as rehabilitation. The M-shaped plantar pressure curve during the stance phase is mainly defined by the loading and unloading slope, 2 maxima, 1 minimum, as well as the force during defined periods. When monitoring gait continuously, walking uphill or downhill could affect this curve in characteristic ways. OBJECTIVE: For walking on a slope, typical changes in the stance phase curve measured by insoles were hypothesized. METHODS: In total, 40 healthy participants of both sexes were fitted with individually calibrated insoles with 16 pressure sensors each and a recording frequency of 100 Hz. Participants walked on a treadmill at 4 km/h for 1 minute in each of the following slopes: -20%, -15%, -10%, -5%, 0%, 5%, 10%, 15%, and 20%. Raw data were exported for analyses. A custom-developed data platform was used for data processing and parameter calculation, including step detection, data transformation, and normalization for time by natural cubic spline interpolation and force (proportion of body weight). To identify the time-axis positions of the desired maxima and minimum among the available extremum candidates in each step, a Gaussian filter was applied (σ=3, kernel size 7). Inconclusive extremum candidates were further processed by screening for time plausibility, maximum or minimum pool filtering, and monotony. Several parameters that describe the curve trajectory were computed for each step. The normal distribution of data was tested by the Kolmogorov-Smirnov and Shapiro-Wilk tests. RESULTS: Data were normally distributed. An analysis of variance with the gait parameters as dependent and slope as independent variables revealed significant changes related to the slope for the following parameters of the stance phase curve: the mean force during loading and unloading, the 2 maxima and the minimum, as well as the loading and unloading slope (all P<.001). A simultaneous increase in the loading slope, the first maximum and the mean loading force combined with a decrease in the mean unloading force, the second maximum, and the unloading slope is characteristic for downhill walking. The opposite represents uphill walking. The minimum had its peak at horizontal walking and values dropped when walking uphill and downhill alike. It is therefore not a suitable parameter to distinguish between uphill and downhill walking. CONCLUSIONS: While patient-related factors, such as anthropometrics, injury, or disease shape the stance phase curve on a longer-term scale, walking on slopes leads to temporary and characteristic short-term changes in the curve trajectory.

Spin-orbit interaction in nanofiber-based Brillouin scattering.

Angular momentum is an important physical property that plays a key role in light-matter interactions, such as spin-orbit interaction. Here, we investigate theoretically and experimentally the spin-orbit interaction between a circularly polarized optical (spin) and a transverse vortex acoustic wave (orbital) using Brillouin backscattering in a silica optical nanofiber. We specifically explore the state of polarization of Brillouin backscattering induced by the TR21 torso-radial vortex acoustic mode that carries an orbital angular momentum. Using a full-vectorial theoretical model, we predict and observe two operating regimes for which the backscattered Brillouin signal is either depolarized or circularly polarized, depending on the input pump polarization. We demonstrate that when the pump is circularly polarized and thus carries a spin angular momentum, the backscattered signal undergoes a handedness reversal of circular polarization due to opto-acoustic spin-orbit interaction and the conservation of overall angular momentum.

Plasmonic Lithium Niobate Mach-Zehnder Modulators.

Lithium niobate Mach-Zehnder modulators (MZMs) are present in a wide range of technologies and though fulfilling the performance and reliability requirements of present applications, they are becoming progressively too bulky, power inefficient, and slow in switching to keep pace with future technological demands. Here, we utilize plasmonics to demonstrate the most efficient (VπL = 0.23 Vcm) lithium niobate MZM to date, consisting of gold nanostripes on lithium niobate that guide both plasmonic modes and electrical signals that control their relative optical phase delay, thereby enabling efficient electro-optic modulation. For high linearity (modulation depth of >2 dB), the proposed MZM inherently operates near its quadrature point by shifting the relative phase of the signal in the interferometric arms. The demonstrated lithium niobate MZM manifests the benefits of employing plasmonics for applications that demand compact (<1 mm2) and fast (>10 GHz) photonic components operating reliably at ambient temperatures.

Disentangling Cathodoluminescence Spectra in Nanophotonics: Particle Eigenmodes vs Transition Radiation.

Cathodoluminescence spectroscopy performed in an electron microscope has proven a versatile tool for analyzing the near- and far-field optical response of plasmonic and dielectric nanostructures. Nevertheless, the transition radiation produced by electron impact is often disregarded in the interpretation of the spectra recorded from resonant nanoparticles. Here we show, experimentally and theoretically, that transition radiation can by itself generate distinct resonances that, depending on the time-of-flight of the electron beam inside the particle, can result from constructive or destructive interference in time. Superimposed on the eigenmodes of the investigated structures, these resonances can distort the recorded spectrum and lead to potentially erroneous assignment of modal characters to the spectral features. We develop an intuitive analogy that helps distinguish between the two contributions. As an example, we focus on the case of silicon nanospheres and show that our analysis facilitates the unambiguous interpretation of experimental measurements on Mie-resonant nanoparticles.

Validating virtual reality for time perception research: Virtual reality changes expectations about the duration of physical processes, but not the sense of time.

Immersive virtual reality (VR) provides a versatile method for investigating human time perception, because it allows the manipulation and control of relevant variables (e.g., the speed of environmental changes) that cannot be modified in the real world. However, an important premise for interpreting the results of VR studies, namely that the method itself does not affect time perception, has received little attention. Here we tested this assumption by comparing timing performance in a real environment and a VR scenario. Participants performed two timing tasks, requiring the production of intervals defined either by numerical values ("eight seconds") or by a physical process ("the time it takes for a bottle to run out when turned over"). We found that the experience of immersive VR exclusively altered judgments about the duration of physical processes, whereas judgments about the duration of abstract time units were unaffected. These results demonstrate that effects of VR on timing performance are not driven by changes in time perception itself, but rather by altered expectations regarding the duration of physical processes. The present study validates the use of VR in time perception research and strengthens the interpretation of changed timing behaviour induced by manipulations within VR.

Optoelectronic Control of Atomic Bistability with Graphene.

We explore the emergence and active control of optical bistability in a two-level atom near a graphene sheet. Our theory incorporates self-interaction of the optically driven atom and its coupling to electromagnetic vacuum modes, both of which are sensitive to the electrically tunable interband transition threshold in graphene. We show that electro-optical bistability and hysteresis can manifest in the intensity, spectrum, and quantum statistics of the light emitted by the atom, which undergoes critical slow-down to steady state. The optically driven atom-graphene interaction constitutes a platform for active control of driven atomic systems in coherent quantum control and atomic physics.

High-Speed Plasmonic Electro-Optic Beam Deflectors.

Highly integrated active nanophotonics addressing both device footprint and operation speed demands is a key enabling technology for the next generation optical networks. Plasmonic systems have proven to be a serious contender to alleviate current performance limitations in electro-optic devices. Here, we demonstrate a plasmonic optical phased array (OPA) consisting of two 10 µm long plasmonic phase shifters, utilized to control the far-field radiation pattern of two subwavelength-separated emitters for aliasing-free beam steering with an angular range of ±5° and flat frequency response up to 18 GHz (with the potential bandwidth of 1.2 THz). Extreme optical and electrostatic field confinement with great spatial overlap results in high phase modulation efficiency (VπL = 0.24 Vcm). The demonstrated approach of using plasmonic lithium niobate technology for optical beam manipulation offers inertia-free, robust, ultracompact, and high-speed beam steering.

Anisotropic second-harmonic generation from monocrystalline gold flakes.

Noble metals with well-defined crystallographic orientation constitute an appealing class of materials for controlling light-matter interactions on the nanoscale. Nonlinear optical processes, being particularly sensitive to anisotropy, are a natural and versatile probe of crystallinity in nano-optical devices. Here we study the nonlinear optical response of monocrystalline gold flakes, revealing a polarization dependence in second-harmonic generation from the {111} surface that is markedly absent in polycrystalline films. Our findings confirm that second-harmonic microscopy is a robust and non-destructive method for probing the crystallographic orientation of gold, and can serve as a guideline for enhancing nonlinear response in plasmonic systems.

On the applicability of quantum-optical concepts in strong-coupling nanophotonics.

Rooted in quantum optics and benefiting from its well-established foundations, strong coupling in nanophotonics has experienced increasing popularity in recent years. With nanophotonics being an experiment-driven field, the absence of appropriate theoretical methods to describe ground-breaking advances has often emerged as an important issue. To address this problem, the temptation to directly transfer and extend concepts already available from quantum optics is strong, even if a rigorous justification is not always available. In this review we discuss situations where, in our view, this strategy has indeed overstepped its bounds. We focus on exciton-plasmon interactions, and particularly on the idea of calculating the number of excitons involved in the coupling. We analyse how, starting from an unfounded interpretation of the term N/V that appears in theoretical descriptions at different levels of complexity, one might be tempted to make independent assumptions for what the number N and the volume V are, and attempt to calculate them separately. Such an approach can lead to different, often contradictory results, depending on the initial assumptions (e.g. through different treatments of V as the-ambiguous in plasmonics-mode volume). We argue that the source of such contradictions is the question itself-How many excitons are coupled?, which disregards the true nature of the coupled components of the system, has no meaning and often not even any practical importance. If one is interested in validating the quantum nature of the system-which appears to be the motivation driving the pursuit of strong coupling with small N-one could instead focus on quantities such as the photon emission rate or the second-order correlation function. While many of the issues discussed here may appear straightforward to specialists, our target audience is predominantly newcomers to the field, either students or scientists specialised in different disciplines. We have thus tried to minimise the occurrence of proofs and overly-technical details, and instead provide a qualitative discussion of analyses that should be avoided, hoping to facilitate further growth of this promising area.

Pharmacological Profile of the Novel Antiepileptic Drug Candidate Padsevonil: Interactions with Synaptic Vesicle 2 Proteins and the GABAA Receptor.

Padsevonil is an antiepileptic drug (AED) candidate synthesized in a medicinal chemistry program initiated to rationally design compounds with high affinity for synaptic vesicle 2 (SV2) proteins and low-to-moderate affinity for the benzodiazepine binding site on GABAA receptors. The pharmacological profile of padsevonil was characterized in binding and electrophysiological experiments. At recombinant SV2 proteins, padsevonil's affinity for SV2A was greater than that of levetiracetam and brivaracetam (pKi 8.5, 5.2, and 6.6, respectively). Unlike the latter AEDs, both selective SV2A ligands, padsevonil also displayed high affinity for the SV2B and SV2C isoforms (pKi 7.9 and 8.5, respectively). Padsevonil's interaction with SV2A differed from that of levetiracetam and brivaracetam; it exhibited slower binding kinetics: dissociation t 1/2 30 minutes from the human protein at 37°C compared with <0.5 minute for levetiracetam and brivaracetam. In addition, its binding was not potentiated by the allosteric modulator UCB1244283. At recombinant GABAA receptors, padsevonil displayed low to moderate affinity (pIC50≤6.1) for the benzodiazepine site, and in electrophysiological studies, its relative efficacy compared with zolpidem (full-agonist reference drug) was 40%, indicating partial agonist properties. In in vivo (mice) receptor occupancy studies, padsevonil exhibited SV2A occupancy at low ED50 (0.2 mg/kg) and benzodiazepine site occupancy at higher doses (ED50 36 mg/kg), supporting in vitro results. Padsevonil's selectivity for its intended targets was confirmed in profiling studies, where it lacked significant effects on a wide variety of ion channels, receptors, transporters, and enzymes. Padsevonil is a first-in-class AED candidate with a unique target profile allowing for presynaptic and postsynaptic activity. SIGNIFICANCE STATEMENT: Padsevonil is an antiepileptic drug candidate developed as a single molecular entity interacting with both presynaptic and postsynaptic targets. Results of in vitro and in vivo radioligand binding assays confirmed this target profile: padsevonil displayed nanomolar affinity for the three synaptic vesicle 2 protein isoforms (SV2A, B, and C) and micromolar affinity for the benzodiazepine binding site on GABAA receptors. Furthermore, padsevonil showed greater affinity for and slower binding kinetics at SV2A than the selective SV2A ligands, levetiracetam, and brivaracetam.

Importance of substrates for the visibility of "dark" plasmonic modes.

Dark plasmonic modes have interesting properties, including longer lifetimes and narrower linewidths than their radiative counterpart, and little to no radiative losses. However, they have not been extensively studied yet due to their optical inaccessibility. In this work, we systematically investigated the dark radial breathing modes (RBMs) in monocrystalline gold nanodisks, specifically their outcoupling behavior into the far-field by cathodoluminescence spectroscopy. Increasing the substrate thickness resulted in an up to 4-fold enhanced visibility. This is attributed to breaking the mirror symmetry by the high-index substrate, creating an effective dipole moment. Furthermore, the resonance energy of the dark RMBs can be easily tuned by varying the nanodisk diameter, making them promising candidates for nanophotonic applications.

Functional characterization of the antiepileptic drug candidate, padsevonil, on GABAA receptors.

OBJECTIVE: The antiepileptic drug candidate, padsevonil, is the first in a novel class of drugs designed to interact with both presynaptic and postsynaptic therapeutic targets: synaptic vesicle 2 proteins and γ-aminobutyric acid type A receptors (GABAA Rs), respectively. Functional aspects of padsevonil at the postsynaptic target, GABAA Rs, were characterized in experiments reported here. METHODS: The effect of padsevonil on GABA-mediated Cl- currents was determined by patch clamp on recombinant human GABAA Rs (α1ß2γ2) stably expressed in a CHO-K1 cell line and on native GABAA Rs in cultured rat primary cortical neurons. Padsevonil selectivity for GABAA R subtypes was evaluated using a two-electrode voltage clamp on recombinant human GABAA Rs (α1-5/ß2/γ2) in Xenopus oocytes. RESULTS: In recombinant GABAA Rs, padsevonil did not evoke Cl- currents in the absence of the agonist GABA. However, when co-administered with GABA at effective concentration (EC)20 , padsevonil potentiated GABA responses by 167% (EC50 138 nmol/L) and demonstrated a relative efficacy of 41% compared with zolpidem, a reference benzodiazepine site agonist. Similarly, padsevonil demonstrated GABA-potentiating activity at native GABAA Rs (EC50 208 nmol/L) in cultured rat cortical neurons. Padsevonil also potentiated GABA (EC20 ) responses in GABAA Rs expressed in oocytes, with higher potency at α1- and α5-containing receptors (EC50 295 and 281 nmol/L) than at α2- and α3-containing receptors (EC50 1737 and 2089 nmol/L). Compared with chlordiazepoxide-a nonselective, full GABAA R agonist-the relative efficacy of padsevonil was 60% for α1ß2γ2, 26% for α2ß2γ2, 56% for α3ß2γ2, and 41% for α5ß2γ2; no activity was observed at benzodiazepine-insensitive α4ß2γ2 receptors. SIGNIFICANCE: Results of functional investigations on recombinant and native neuronal GABAA Rs show that padsevonil acts as a positive allosteric modulator of these receptors, with a partial agonist profile at the benzodiazepine site. These properties may confer better tolerability and lower potential for tolerance development compared with classic benzodiazepines currently used in the clinic.

On-Chip Detection of Optical Spin-Orbit Interactions in Plasmonic Nanocircuits.

On-chip manipulating and controlling the temporal and spatial evolution of light are of crucial importance for information processing in future planar integrated nanophotonics. The spin and orbital angular momentum of light, which can be treated independently in classical macroscopic geometrical optics, appear to be coupled on subwavelength scales. We use spin-orbit interactions in a plasmonic achiral nanocoupler to unidirectionally excite surface plasmon polariton modes propagating in seamlessly integrated plasmonic slot waveguides. The spin-dependent flow of light in the proposed nanophotonic circuit allows on-chip electrical detection of the spin state of incident photons by integrating two germanium-based plasmonic-waveguide photodetectors. Consequently, our device serves as a compact (∼6 × 18 µm2) electrical sensor for photonic spin Hall dynamics. The demonstrated configuration opens new avenues for developing highly integrated polarization-controlled optical devices that would exploit the spin-degree of freedom for manipulating and controlling subwavelength optical modes in nanophotonic systems.

The DnaJ-Like Zinc-Finger Protein HCF222 Is Required for Thylakoid Membrane Biogenesis in Plants.

To understand the biogenesis of the thylakoid membrane in higher plants and to identify auxiliary proteins required to build up this highly complex membrane system, we have characterized the allelic nuclear mutants high chlorophyll fluorescence222-1 (hcf222-1) and hcf222-2 and isolated the causal gene by map-based cloning. In the ethyl methanesulfonate-induced mutant hcf222-1, the accumulation of the cytochrome b6f (Cytb6f) complex was reduced to 30% compared with the wild type. Other thylakoid membrane complexes accumulated to normal levels. The T-DNA knockout mutant hcf222-2 showed a more severe defect with respect to thylakoid membrane proteins and accumulated only 10% of the Cytb6f complex, accompanied by a reduction in photosystem II, the photosystem II light-harvesting complex, and photosystem I. HCF222 encodes a protein of 99 amino acids in Arabidopsis (Arabidopsis thaliana) that has similarities to the cysteine-rich zinc-binding domain of DnaJ chaperones. The insulin precipitation assay demonstrated that HCF222 has disulfide reductase activity in vitro. The protein is conserved in higher plants and bryophytes but absent in algae and cyanobacteria. Confocal fluorescence microscopy showed that a fraction of HCF222-green fluorescent protein was detectable in the endoplasmic reticulum but that it also could be recognized in chloroplasts. A fusion construct of HCF222 containing a plastid transit peptide targets the protein into chloroplasts and was able to complement the mutational defect. These findings indicate that the chloroplast-targeted HCF222 is indispensable for the maturation and/or assembly of the Cytb6f complex and is very likely involved in thiol-disulfide biochemistry at the thylakoid membrane.

On-chip multi-stage optical delay based on cascaded Brillouin light storage.

Storing and delaying optical signals plays a crucial role in data centers, phased array antennas, communication, and future computing architectures. Here, we show a delay scheme based on cascaded Brillouin light storage that achieves multi-stage delay at arbitrary positions within a photonic integrated circuit. Importantly these multiple resonant transfers between the optical and acoustic domain are controlled solely via external optical control pulses, allowing cascading of the delay without the need of aligning multiple structural resonances along the optical circuit.

Accordance of Online Health Information on Prostate Cancer with the European Association of Urology Guidelines.

BACKGROUND: The internet is an emerging source of information for prostate cancer (PCa) patients. Since little is known about the quality of information on PCa provided online, we investigated its accordance to the latest European Association of Urology (EAU) guidelines. METHODS: A total of 89 German web pages were included for analysis. A quality model classifying the provider of information and its expertise was introduced. Correctness of provided information was systematically compared to the EAU guidelines. RESULTS: Information was provided by medical experts (41%), media (11%), and pharmaceutical companies (6%). Certificates were found in 23% with a significantly higher rate if provided by medical experts (p = 0.003). The minority of web pages showed information in accordance with the EAU guidelines regarding screening (63%), diagnosis (32%), classification (39%), therapy (36%), complications (8%), and follow-up (27%). Web pages by medical experts as well as websites with any kind of certification showed a significantly higher guideline conformity regarding diagnosis (p = 0.027, p = 0.002), therapy (p = 0.010, p = 0.011), follow-up (p = 0.005, p < 0.001), and availability of references (p = 0.017, p = 0.003). CONCLUSIONS: The present study reveals that online health information on PCa lacks concordance to current guidelines. Certified websites or websites provided by medical experts showed a significantly higher quality and accordance with guidelines.

Lasing in ring resonators by stimulated Brillouin scattering in the presence of nonlinear loss.

We theoretically investigate lasing due to stimulated Brillouin scattering in integrated ring resonators. We give analytic expressions and numerical calculations for the lasing threshold for rings in the presence of for both linear and nonlinear loss. We demonstrate the operation of the ring in the different regimes of amplification and lasing, and show how these regimes depend on the coupling to the ring and on the nonlinear parameters. In the case of nonlinear losses, we find that there can exist an upper threshold to the lasing regime where the losses are dominated by free-carrier absorption. We also find that nonlinear losses can inhibit Brillouin lasing entirely for certain ranges of coupling parameters, and we show how the correct ranges of coupling parameters can be calculated and optimized for the design of integrated Brillouin lasers.

Activity of the anticonvulsant lacosamide in experimental and human epilepsy via selective effects on slow Na+ channel inactivation.

OBJECTIVE: In human epilepsy, pharmacoresistance to antiepileptic drug therapy is a major problem affecting ~30% of patients with epilepsy. Many classical antiepileptic drugs target voltage-gated sodium channels, and their potent activity in inhibiting high-frequency firing has been attributed to their strong use-dependent blocking action. In chronic epilepsy, a loss of use-dependent block has emerged as a potential cellular mechanism of pharmacoresistance for anticonvulsants acting on voltage-gated sodium channels. The anticonvulsant drug lacosamide (LCM) also targets sodium channels, but has been shown to preferentially affect sodium channel slow inactivation processes, in contrast to most other anticonvulsants. METHODS: We used whole-cell voltage clamp recordings in acutely isolated cells to investigate the effects of LCM on transient Na+ currents. Furthermore, we used whole-cell current clamp recordings to assess effects on repetitive action potential firing in hippocampal slices. RESULTS: We show here that LCM exerts its effects primarily via shifting the slow inactivation voltage dependence to more hyperpolarized potentials in hippocampal dentate granule cells from control and epileptic rats, and from patients with epilepsy. It is important to note that this activity of LCM was maintained in chronic experimental and human epilepsy. Furthermore, we demonstrate that the efficacy of LCM in inhibiting high-frequency firing is undiminished in chronic experimental and human epilepsy. SIGNIFICANCE: Taken together, these results show that LCM exhibits maintained efficacy in chronic epilepsy, in contrast to conventional use-dependent sodium channel blockers such as carbamazepine. They also establish that targeting slow inactivation may be a promising strategy for overcoming target mechanisms of pharmacoresistance.

Brivaracetam does not modulate ionotropic channels activated by glutamate, γ-aminobutyric acid, and glycine in hippocampal neurons.

Brivaracetam (BRV) is a selective, high-affinity ligand for synaptic vesicle protein 2A (SV2A), recently approved as adjunctive treatment for drug-refractory partial-onset seizures in adults. BRV binds SV2A with higher affinity than levetiracetam (LEV), and was shown to have a differential interaction with SV2A. Because LEV was reported to interact with multiple excitatory and inhibitory ligand-gated ion channels and that may impact its pharmacological profile, we were interested in determining whether BRV directly modulates inhibitory and excitatory ionotropic receptors in central neurons. Voltage-clamp experiments were performed in primary cultures of mouse hippocampal neurons. At a supratherapeutic concentration of 100 µm, BRV was devoid of any direct effect on currents gated by γ-aminobutyric acidergic type A, glycine, kainate, N-methyl-d-aspartate, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid. Similarly to LEV, BRV reveals a potent ability to oppose the action of negative modulators on the inhibitory receptors. In conclusion, these results show that BRV contrasts with LEV by not displaying any direct action on inhibitory or excitatory postsynaptic ligand-gated receptors at therapeutic concentrations and thereby support BRV's role as a selective SV2A ligand. These findings add further evidence to the validity of SV2A as a relevant antiepileptic drug target and emphasize the potential for exploring further presynaptic mechanisms as a novel approach to antiepileptic drug discovery.