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Lafora disease (LD) is a syndrome of progressive myoclonic epilepsy and cumulative neurocognitive deterioration caused by recessively inherited genetic lesions of EPM2A (laforin) or NHLRC1 (malin). Neuropsychiatric symptomatology in LD is thought to be directly downstream of neuronal and astrocytic polyglucosan aggregates, termed Lafora bodies (LBs), which faithfully accumulate in an age‐dependent manner in all mouse models of LD. In this study, we applied home‐cage monitoring to examine the extent of neurobehavioral deterioration in a model of malin‐deficient LD as a means to identify robust preclinical endpoints that may guide the selection of novel genetic treatments. At 6 weeks, ∼6–7 months, and ∼12 months of age, malin‐deficient mice ("KO") and wild‐type (WT) littermates underwent a standardized home‐cage behavioral assessment designed to non‐obtrusively appraise features of rest/arousal, consumptive behaviors, risk aversion, and voluntary wheel‐running. At all timepoints, and over a range of metrics that we report transparently, WT and KO mice were essentially indistinguishable. In contrast, within WT mice compared across the same timepoints, we identified age‐related nocturnal hypoactivity, diminished sucrose preference, and reduced wheel‐running. Neuropathological examinations in subsets of the same mice revealed expected age‐dependent LB accumulation, gliosis, and microglial activation in cortical and subcortical brain regions. At 12 months of age, despite the burden of neocortical LBs, we did not identify spontaneous seizures during an electroencephalographic (EEG) survey, and KO and WT mice exhibited similar spectral EEG features. However, in an in vitro assay of neocortical function, paroxysmal bursts of network activity (UP states) in KO slices were more prolonged at 3 and 6 months of age, but similar to WT at 12 months. KO mice displayed a distinct response to pentylenetetrazole, with a greater incidence of clonic seizures and a more pronounced postictal suppression of movement, feeding, and drinking behavior. Together, these results highlight the clinicopathologic dissociation in a mouse model of LD, where the accrual of LBs may latently modify cortical circuit function and seizure threshold without clinically meaningful changes in home‐cage behavior. Our findings allude to a delay between LB accumulation and neurobehavioral decline in LD: one that may provide a window for treatment, and whose precise duration may be difficult to ascertain within the typical lifespan of a laboratory mouse. [ABSTRACT FROM AUTHOR]

Highlights • MMF showed marked reduction in seizure severity in a dose-dependent manner. • MMF reversed epilepsy-induced cognition deficit and behavioral impairments. • There was decreased neuronal death and axonal sprouting following MMF treatment. • MMF showed reduction in the hippocampus protein level of mTOR, S6 and pS6. • MMF treatment reduced hippocampal mRNA expression of PI3K/AKT/mTOR pathway related genes. Abstract The role of neuroinflammatory mediators has been well established in the pathogenesis of temporal lobe epilepsy (TLE) and associated neurobehavioral comorbidities. Mycophenolate mofetil (MMF) is commonly used as an immunosuppressant in organ transplantations. Its neuroprotective effect is well explored in different preclinical and clinical studies. The present study was designed to investigate the effect of MMF in rat model of lithium pilocarpine (LiPc)-induced spontaneous recurrent seizures and its associated neurobehavioral comorbidities. MMF treatment showed a dose-dependent decrease in seizure severity and reduced aggression in epileptic rats. There was marked improvement in spatial and recognition memory functions, along with substantial decrease in depression-like behavior in MMF treated epileptic rats. There was considerable decrease in mossy fiber sprouting in the dentate gyrus and the cornu ammonis 3 regions of the hippocampus, along with reduction in neuronal death in the treated groups. Furthermore, the hippocampal mRNA level of IL-1β , IL-2 , PI3K , AKT , HIF-1α , RAPTOR , mTOR , Rps6kb1 and Rps6 was found to be decreased in MMF treated animals. mTOR, S6, pS6 and GFAP protein expression was decreased, whereas NeuN was increased in the rat hippocampus of the treated animals. The results concluded that MMF suppress recurrent seizures, and improves its associated behavioral impairments and cognitive deficit in rat model of TLE. The observed effects of MMF be correlated with the inhibition of IL-2 and IL-1β linked PI3K/AKT/mTOR signaling pathway hyperactivation. [ABSTRACT FROM AUTHOR]

Ethnopharmacological relevance Ginkgo biloba L. (Ginkgoaceae) has been widely used in traditional medicine for variety of neurological conditions particularly behavioral and memory impairments. Aim of the study The present study was envisaged to explore the effect of a standardized fraction of Ginkgo biloba leaves ( GBbf ) in rat model of lithium-pilocarpine induced spontaneous recurrent seizures, and associated behavioral impairments and cognitive deficit. Materials and methods Rats showing appearance of spontaneous recurrent seizures following lithium pilocarpine (LiPc)-induced status epilepticus (SE) were treated with different doses of GBbf or vehicle for subsequent 4 weeks. The severity of seizures and aggression in rats were scored following treatment with GBbf . Further, open field, forced swim, novel object recognition and Morris water maze tests were conducted. Histopathological, protein levels and gene expression studies were performed in the isolated brains. Results Treatment with GBbf reduced seizure severity score and aggression in epileptic animals. Improved spatial cognitive functions and recognition memory, along with reduction in anxiety-like behavior were also observed in the treated animals. Histopathological examination by Nissl staining showed reduction in neuronal damage in the hippocampal pyramidal layer. The dentate gyrus and Cornu Ammonis 3 regions of the hippocampus showed reduction in mossy fiber sprouting. GBbf treatment attenuated ribosomal S6 and pS6 proteins, and hippocampal mTOR , Rps6 and Rps6kb1 mRNA levels. Conclusions The results of present study concluded that GBbf treatment suppressed lithium-pilocarpine induced spontaneous recurrent seizures severity and incidence with improved cognitive functions, reduced anxiety-like behavior and aggression. The effect was found to be due to inhibition of mTOR pathway hyperactivation linked with recurrent seizures. [ABSTRACT FROM AUTHOR]

Crocin is a pharmacologically active carotenoid pigment mainly present in the stigmas of Crocus sativus L. (Iridaceae). It has been well explored in experimental animal models of cognitive impairments, depression, anxiety and epilepsy. This study was designed to understand the effect of crocin on pentylenetetrazol (PTZ)-induced kindling development and its associated cognitive deficit in mouse. Crocin treatment at 5, 10 and 20 mg/kg p.o. doses showed a marked reduction in severity of PTZ-induced seizures. There was an increase in novel object preference index and discrimination ratio in the crocin-treated groups in the novel object recognition test. Its treatment also increased percentage spontaneous alternations in T-maze test at all the tested doses. Histopathological examination by Nissl staining showed a reduction in dark neurons in the hippocampal pyramidal layer of crocin-treated animals in contrast to vehicle control, indicating a decrease in neuronal damage. Biochemical estimations showed a significant increase in superoxide dismutase activity and reduced reactive oxygen species (ROS) in the hippocampus of crocin-treated animals. Immunohistochemistry results revealed attenuation in the levels of nuclear factor-κB (NF-κB) and phosphorylated NF-κB in the hippocampal sections of crocin-treated animals. The results of this study concluded that crocin treatment increased seizure threshold, thus inhibiting PTZ-induced kindling development and improving cognitive functions. The effect was found to be due to suppression of seizure-induced ROS generation and its linked NF-κB pathway-associated neuronal damage. [ABSTRACT FROM AUTHOR]

Steady state, time-resolved fluorescenceand NMR experiments arecarried out to gain deeper insights into the structure–propertycorrelation in structurally similar monocationic and dicationic room-temperatureionic liquids (RTILs). The excitation wavelength dependent fluorescenceresponse of fluorophore in 1-methy-3-propyllimidazolium bis(trifluoromethylsulfonyl)amide[C3MIm][NTf2] is found to be different fromthat of 1,6-bis(3-methylimidazolium-1-yl)hexane bis(trifluoromethylsulfonyl)amide[C6(MIm)2][NTf2]2and1-hexyl-3-methylimidazolium bis(trifluoromethylsulfonyl)amide [C6MIm][NTf2]. The outcomes of the present solventdynamics study in [C3MIm][NTf2] when comparedwith those in [C6(MIm)2][NTf2]2and in [C6MIm][NTf2] from our previousstudies (Phys. Chem. Chem. Phys.2014, 16, 1291812928) indicate the involvementof dipolar rotation of imidazolium cation during solvation. To correlatethe findings of solvation dynamics study with the dipolar rotationof the imidazolium ring, pulsed-field gradient (PFG)-NMR techniquefor translational diffusion coefficient measurement and 1H as well as 19F spin–lattice relaxation measurementsare employed. NMR investigation reveals that an ultrafast componentof solvation can be related to the dipolar rotation of imidazoliumcation; hence, the role of dipolar rotation of cations in governingthe dynamics of solvation in ILs cannot be ignored. Analysis of therotational relaxation dynamics data by the Stokes–Einstein–Debyehydrodynamic theory unveils distinctive features of solute–solventinteraction in [C3MIm][NTf2] and [C6(MIm)2][NTf2]2. [ABSTRACT FROM AUTHOR]

A dynamic voltage restorer (DVR) is a power-electronic controller that can protect sensitive loads from disturbances in the supply system. In this paper, it is demonstrated that this device can tightly regulate the voltage at the load terminal against imbalance or harmonic in the source side. The behavior of the device is studied through steady-state analysis, and limits to achievable performance are found. This analysis is extended to the study of transient operation where the generation of the reference voltage of the DVR is discussed. Once the reference signals are generated, they are tracked using a switching band scheme. A suitable structure in which the DVR is realized by voltage-source inverters (VSIs) is also discussed. Particular emphasis to the rating of this device is provided. Extensive simulation results are included to illustrate the operating principles of a DVR. [ABSTRACT FROM AUTHOR]

• LY294002 pretreatment reduced the hyperactive responses in PTZ exposed larvae. • Latency to first clonic-like seizures increased and c-fos expression decreased in LY294002 treated larvae. • PTZ evoked seizure severity and occurrence decreased in adult zebrafish following LY294002 treatment. • LY294002 treatment decreased brain mRNA expression of PI3K/AKT/mTOR signaling pathway linked genes. The role of PI3K/AKT/mTOR signalling pathway has been widely deciphered in pathogenesis of epilepsy. LY294002 is a selective inhibitor of phosphatidylinositol-3-kinase (PI3K). The present study was designed to explore the anticonvulsant potential of LY294002 in a zebrafish model of pentylenetetrazole (PTZ)-mediated convulsions. Zebrafish larvae at 7 dpf (days post fertilization) were pre-incubated with varying concentrations of LY294002, prior to PTZ exposure. The adult zebrafish were also exposed to PTZ after intraperitoneal injection with different concentrations of LY294002, followed by gene expression studies in the brain. The hyperactive responses indicated by total distance travelled and the mean speed of larva was drastically decreased, whereas latency to first clonic-like seizure was increased following LY294002 pre-treatment. Additionally, a marked decrease in c-fos expression was also observed in the larvae group exposed to LY294002 in comparison to control. Furthermore, PTZ evoked seizure severity was considerably decreased, while latency to clonic-like seizure was increased in adult zebrafish group treated with 100 nM of LY294002. Furthermore, the occurrence of tonic-like seizures was also reduced in the adult zebrafish treated with LY294002. The mRNA levels of PIK3CA, PIK3R1, AKT1, mTOR , Rps6 and Rps6kb1 in adult zebrafish brain was significantly reduced as compared to vehicle control group. Our results provided conclusive support for the anticonvulsant potential of LY294002. [ABSTRACT FROM AUTHOR]

Pyrrolone-fused benzosuberene (PBS) compounds were semi-synthesized from α,β,γ-Himachalenes extracted from the essential oil of Cedrus deodara following amino-vinyl-bromide substituted benzosuberenes as intermediates. These PBSs compounds classified as an attractive source of therapeutics. The α-isoform of PI3K which is a pivotal modulator of PI3K/AKT/mTOR signaling pathway, responsible for neurological disorders like epilepsy, found as a potential target molecule against these 17 semi-synthesized PBS compounds using in silico ligand-based pharmacophore mapping and target screening. The compounds screened using binding affinities, ADMET properties, and toxicity that were accessed by in silico docking simulations and pharmacokinetics profiling. Ultimately two compounds viz., PBS-8 and PBS-9 were selected for further in vivo evaluation using a zebrafish (Danio rerio) model of pentylenetetrazol (PTZ)-induced clonic convulsions. Additionally, gene expression studies performed for the genes of the PI3K/AKT/mTOR pathway which further validated our results. In conclusion, these findings suggested that PBS-8 is a promising candidate that could bedeveloped as a potential antiepileptic. [ABSTRACT FROM AUTHOR]

Effect of residual Doppler averaging on the probe absorption in an alkali vapor medium in the presence of a coherent pump beam is studied analytically for the Ξ type system. A coherent probe field is assumed to connect the ground level with the intermediate level whereas a coherent control beam is supposed to act between the intermediate energy level and the uppermost level. Optical Bloch equations (OBE) for a three-level Ξ type system and a four-level Ξ type system are derived by using density matrix formalism. These equations are solved by an analytic method to determine the probe response, which not only depends on the wavelength difference between the control (pump) field and the probe field but shows substantially different features depending on whether the wavelength of the control field is greater than that of the probe field or the reverse. The effect of temperature on probe response is also shown. Enhancement in probe absorption and additional features are noticed under a strong probe limit at room temperature. The four-level Ξ type system has two ground levels and this leads to substantial modification in the simulated probe absorption as compared to the three-level system. [ABSTRACT FROM AUTHOR]

Coherent probe field (LA) propagation through an eight-level inverted Y-type atomic system, in the presence of two additional coherent radiation fields termed the field LC (control or pump field) and the field LB (repump field), is investigated by using the parameters of 87Rb transitions. The system has two ground energy levels, four intermediate energy levels, and two uppermost energy levels. A theoretical model based on the density matrix method is used for numerical simulation of the probe response under different conditions. Simulated probe absorption spectra under a Doppler-free condition as well as under thermal averaging exhibit electromagnetically induced transparency (EIT). The position and line shape of this EIT profile change with different detunings of the control and repump fields. When the three coherent fields share a common level, a funnel-like EIT window appears in the simulated probe absorption curve. Velocity selective optically pumped absorption peaks are seen in the simulated probe response at room temperature. [ABSTRACT FROM AUTHOR]

We report the occurrence of electromagnetically induced transparency (EIT) in the simulated probe response signal for a four-level inverted-Y type system that is being acted upon by a weak coherent probe field, a strong coherent pump field and a coherent repump field. There are two ground energy levels, one intermediate energy level and one uppermost energy level. The weak probe field couples the lowest ground level to the intermediate level whereas the repump field connects the other ground level with the intermediate level. The strong control field couples the intermediate level with the uppermost energy level, thereby forming an inverted-Y type system. The density matrix based theoretical model has been developed and solved analytically for this four-level system and the probe response signal has been simulated at different values of the control and repump Rabi frequencies, control and repump frequency detunings and under both Doppler-free and Doppler-broadened conditions using the parameters of 87Rb D2 transition. Extremely low line width (few tens of kHz) for the EIT signal has been noticed under thermal averaging for copropagating probe, control and repump field configuration. The EIT signal is found to be immune to the variation in the control Rabi frequency. [ABSTRACT FROM AUTHOR]

We report the observation of electromagnetically induced transparency (EIT) in a six-level Λ-type system in atomic Rb vapor containing both 87Rb and 85Rb. The experimental observation includes five velocity selective optically pumped (VSOP) absorption dips for both 87Rb and 85Rb. The EIT signal appears on the background of one such VSOP absorption dips. The measured EIT linewidth () shows sub-natural ( ) values for both lower and higher values of pump Rabi-frequencies. The density matrix based theoretical model for the six-level system is developed and solved numerically by taking into account the Doppler broadening. A complete analytical solution (non perturbative) for a three level Λ-type system has been obtained and compared with the experimentally observed sub-natural EIT linewidth. The simulated spectra are in good agreement with the experimental findings. [ABSTRACT FROM AUTHOR]

Punica granatum L. (Punicaceae) peel is often considered as a food waste in-spite of its high bioactive metabolite composition. Primarily it is rich in therapeutically active phenolics that act on multiple cellular sites, through diverse mechanisms. Hence, the present study was envisaged to investigate the effect of standardised peel extract of P. granatum against isoproterenol (ISO)-induced myocardial infarction (MI). ISO administration at a dose of 150 mg/kg; s.c. , twice at 24 h interval resulted in electrocardiographic abnormalities with increased heart weight and myocardial tissue damage signifying MI. Pretreatment with the extract at 50, 100 and 200 mg/kg; p.o. , for 21 days prior to ISO intoxication (30 min prior to intoxication on day 22 and 23) attenuated the observed changes, along with increased myocardial tissue superoxide dismutase activity, reduced glutathione and nitrite levels, and decreased lipid peroxidation. The extract treated groups also showed reduced serum marker enzymes of MI, showing maximum effect at highest tested dose. Immunohistochemical studies revealed increased myocardial expression of nuclear factor erythroid 2-related factor 2 (Nrf2), endothelial nitric oxide synthase (eNOS) and Bcl-2 proteins in the extract treated groups with decreased Bax expression. From the results it can be concluded that the extract pretreatment prevents ISO-induced MI through increased myocardial expression of eNOS, leading to nitric oxide-mediated Nrf2 activation, thus upregulating antioxidant mechanisms, along with inhibition of apoptosis. [ABSTRACT FROM AUTHOR]

Abstract: Non(anti)commutativity in an open free superstring and also one moving in a background antisymmetric tensor field is investigated. In both cases, the non(anti)commutativity is shown to be a direct consequence of the nontrivial boundary conditions which, contrary to several approaches, are not treated as constraints. The above non(anti)commutative structures lead to new results in the algebra of superconstraints which still remain involutive, indicating the internal consistency of our analysis. [Copyright &y& Elsevier]

• Exposure of 1.25 mM PTZ for 22 days induced kindling-like state in adult zebrafish. • The expression of c-fos, crebbpa, and crebbpb increased in kindled fish brain. • The kindled fish brain showed an increased level of glutamate/GABA. • Valproic acid treatment inhibited the development of the kindling-like state in fish. • Valproic acid reduced the severity of seizures mediated by PTZ in kindled fish. Zebrafish has emerged as a potential animal model of acute convulsion for early screening of antiepileptic agents. There is a need for alternative chronic zebrafish models of epilepsy with more correlation to the clinical condition. Adult zebrafish were repeatedly exposed to subeffective concentrations of pentylenetetrazole (PTZ), until appearance to tonic-clonic seizures, considered as kindled. Valproic acid (VPA) exposure was given during kindling and in kindled fish in 2 different groups. The neurotransmitters level and expression of the genes associated with kindling were studied in the fish brain. There was an increase in seizure severity score at 1.25 mM concentration of PTZ, and 66.66 % of fish achieved kindling after 22 days' exposure. A marked increase in c-fos , crebbpa and crebbpb expression, and glutamate/GABA level was observed in the brain of kindled fish. VPA inhibited the induction of PTZ-mediated kindling and reduced seizure severity in kindled fish. In contrast to an existing adult zebrafish kindling method, the present protocol is of longer duration, with more similarity to clinical epilepsy. Moreover, the induction of kindling involves a simple non-invasive technique without the use of anesthesia. The protocol can be used for evaluation of both antiepileptic and antiepileptogenic agents. Repeated exposure of 1.25 mM PTZ induced kindling in zebrafish, altering the brain neurotransmitter levels and gene expression. Inhibition of kindling induction and decrease in seizures in normal and kindled fish, respectively by VPA validated application of the model for preclinical testing of agents against epilepsy. [ABSTRACT FROM AUTHOR]

The absorption features of a probe field propagating through a four-level N-type atomic system in the presence of two coherent radiation fields is studied analytically by using a density matrix formulation. The system has two ground levels and two excited levels. A weak probe laser couples the upper ground level to the lower excited level whereas a strong control field connects the lower ground level to the lower excited level. The coupling field acts between the upper ground level and the upper excited level. The transition parameters of the 87Rb D1 line have been used to simulate the probe response. The simulated probe absorption shows a gain-like structure depending on the relative field intensities. The spectral features of the probe response exhibit substantial differences under thermal averaging as compared to a Doppler-free condition. The splitting of simulated probe absorption can be explained by the dressed state model. Electromagnetically induced absorption (EIA) is observed in the simulated probe response curve when the spontaneous decay of the population from the uppermost excited state to the lower ground state is absent. [ABSTRACT FROM AUTHOR]

We have addressed the microscopic transport mechanism at the switching or ‘on–off’ transition in transition metal dichalcogenide (TMDC) field-effect transistors (FETs), which has been a controversial topic in TMDC electronics, especially at room temperature. With simultaneous measurement of channel conductivity and its slow time-dependent fluctuation (or noise) in ultrathin WSe2 and MoS2 FETs on insulating SiO2 substrates where noise arises from McWhorter-type carrier number fluctuations, we establish that the switching in conventional backgated TMDC FETs is a classical percolation transition in a medium of inhomogeneous carrier density distribution. From the experimentally observed exponents in the scaling of noise magnitude with conductivity, we observe unambiguous signatures of percolation in a random resistor network, particularly, in WSe2 FETs close to switching, which crosses over to continuum percolation at a higher doping level. We demonstrate a powerful experimental probe to the microscopic nature of near-threshold electrical transport in TMDC FETs, irrespective of the material detail, device geometry, or carrier mobility, which can be extended to other classes of 2D material-based devices as well. [ABSTRACT FROM AUTHOR]

Graphene constitutes one of the key elements in many functional van der Waals heterostructures. However, it has negligible optical visibility due to its monolayer nature. Here we study the visibility of graphene in various van der Waals heterostructures and include the effects of the source spectrum, oblique incidence and the spectral sensitivity of the detector to obtain a realistic model. A visibility experiment is performed at different wavelengths, resulting in a very good agreement with our calculations. This allows us to reliably predict the conditions for better visibility of graphene in van der Waals heterostructures. The framework and the codes provided in this work can be extended to study the visibility of any 2D material within an arbitrary van der Waals heterostructure. [ABSTRACT FROM AUTHOR]