Chronobiology of Epilepsy

A fine balance between neuronal excitation and inhibition governs the physiological state of the brain. It has been hypothesized that when this balance is lost as a result of excessive excitation or reduced inhibition, pathological states such as epilepsy emerge. Decades of investigation have shown this to be true in vitro. However, in vivo evidence of the emerging imbalance during the "latent period" between the initiation of injury and the expression of the first spontaneous behavioral seizure has not been demonstrated. Here, we provide the first demonstration of this emerging imbalance between excitation and inhibition in vivo by employing long term, high temporal resolution, and continuous local field recordings from microelectrode arrays implanted in an animal model of limbic epilepsy. We were able to track both the inhibitory and excitatory postsynaptic field activity during the entire latent period, from the time of injury to the occurrence of the first spontaneous epileptic seizure. During this latent period we observe a sustained increase in the firing rate of the excitatory postsynaptic field activity, paired with a subsequent decrease in the firing rate of the inhibitory postsynaptic field activity within the CA1 region of the hippocampus. Firing rates of both excitatory and inhibitory CA1 field activities followed a circadian- like rhythm, which is locked near in-phase in controls and near anti-phase during the latent period. We think that these observed changes are implicated in the occurrence of spontaneous seizure onset following injury

Negative tunneling magnetoresistance by canted magnetization in MgO/NiO tunnel barriers

The influence of insertion of an ultra-thin NiO layer between the MgO barrier and ferromagnetic electrode in magnetic tunnel junctions has been investigated by measuring the tunneling magnetoresistance and the X-ray magnetic circular dichroism (XMCD). The magnetoresistance shows a high asymmetry with respect to bias voltage, giving rise to a negative value of -16% at 2.8 K. We attribute this to the formation of non-collinear spin structures in the NiO layer as observed by XMCD. The magnetic moments of the interface Ni atoms tilt from the easy axis due to exchange interaction and the tilting angle decreases with increasing the NiO thickness. The experimental observations are further support by non-collinear spin density functional theory

ASASSN-16ae: A Powerful White-Light Flare on an Early-L Dwarf

We report the discovery and classification of SDSS~J053341.43+001434.1 (SDSS0533), an early-L dwarf first discovered during a powerful $\Delta V < -11$ magnitude flare observed as part of the ASAS-SN survey. Optical and infrared spectroscopy indicate a spectral type of L0 with strong H$\alpha$ emission and a blue NIR spectral slope. Combining the photometric distance, proper motion, and radial velocity of SDSS0533 yields three-dimensional velocities of $(U,V,W)=(14\pm13,-35\pm14,-94\pm22)$~km~s$^{-1}$, indicating that it is most likely part of the thick disk population and probably old. The three detections of SDSS0533 obtained during the flare are consistent with a total $V$-band flare energy of at least $4.9\times10^{33}$~ergs (corresponding to a total thermal energy of at least $E_{\rm tot}>3.7\times10^{34}$~erg), placing it among the strongest detected M dwarf flares. The presence of this powerful flare on an old L0 dwarf may indicate that stellar-type magnetic activity persists down to the end of the main sequence and on older ML transition dwarfs.Comment: 7 pages, 3 tables, 2 figures; accepted to ApJ Letters; updated to reflect referee response and proof correction

Crazing of nanocomposites with polymer-tethered nanoparticles

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A genetic diversity study of antifungal Lactobacillus plantarum isolates

Lactobacillus plantarum is a lactic acid bacterium commonly found on fruits and vegetables and also used in a variety of food fermentations. Strains from this species are also regularly reported as having antifungal or probiotic activity. Genotyping methods can be used to differentiate strains of the same species thus determining if strains are related or not. However for L.\ua0plantarum, the currently used methods have limitations including DNA band profile interpretation difficulty and cost. In this study, a new genotyping method based on multi-locus variable number tandem repeat analysis (MLVA) was developed and compared to a previously reported randomly amplified polymorphic DNA-PCR (RAPD-PCR) method for L.\ua0plantarum. With a selection of 13 antifungal strains of L.\ua0plantarum isolated from heterogeneous sources (cheese, silage, sauerkraut, vegetables and a probiotic product), RAPD-PCR revealed 9 different profiles resulting in a Hunter-Gaston discrimination index (D-value) of 0.94. The new MLVA method which compares the lengths of 4 repetitive regions within LPXTG motif-containing surface protein genes differentiated the 13\ua0L.\ua0plantarum strains into 10 different subtypes leading to a D-value of 0.95. Interestingly 11 additional L.\ua0plantarum isolates obtained in a previous study during a screen for antifungal activity against the common cheese spoilage mould Penicillium commune all possessed the same RAPD-PCR and MLVA profile as each other and the commercial probiotic strain L.\ua0plantarum 299v. This study demonstrates that the new MLVA method can be used to simply and inexpensively differentiate L.\ua0plantarum strains and provide information regarding strain relatedness and thus potential insight into strain properties

Stable reduction of CCR5 by RNAi through hematopoietic stem cell transplant in non-human primates

RNAi is a powerful method for suppressing gene expression that has tremendous potential for therapeutic applications. However, because endogenous RNAi plays a role in normal cellular functions, delivery and expression of siRNAs must be balanced with safety. Here we report successful stable expression in primates of siRNAs directed to chemokine (c-c motif) receptor 5 (CCR5) introduced through CD34+ hematopoietic stem/progenitor cell transplant. After hematopoietic reconstitution, to date 14 months after transplant, we observe stably marked lymphocytes expressing siRNAs and consistent down-regulation of chemokine (c-c motif) receptor 5 expression. The marked cells are less susceptible to simian immunodeficiency virus infection ex vivo. These studies provide a successful demonstration that siRNAs can be used together with hematopoietic stem cell transplant to stably modulate gene expression in primates and potentially treat blood diseases such as HIV-1

Targeting the differential addiction to anti-apoptotic BCL-2 family for cancer therapy

AbstractBCL-2 family proteins are central regulators of mitochondrial apoptosis and validated anti-cancer targets. Using small cell lung cancer (SCLC) as a model, we demonstrated the presence of differential addiction of cancer cells to anti-apoptotic BCL-2, BCL-XL or MCL-1, which correlated with the respective protein expression ratio. ABT-263 (navitoclax), a BCL-2/BCL-XL inhibitor, prevented BCL-XL from sequestering activator BH3-only molecules (BH3s) and BAX but not BAK. Consequently, ABT-263 failed to kill BCL-XL-addicted cells with low activator BH3s and BCL-XL overabundance conferred resistance to ABT-263. High-throughput screening identified anthracyclines including doxorubicin and CDK9 inhibitors including dinaciclib that synergized with ABT-263 through downregulation of MCL-1. As doxorubicin and dinaciclib also reduced BCL-XL, the combinations of BCL-2 inhibitor ABT-199 (venetoclax) with doxorubicin or dinaciclib provided effective therapeutic strategies for SCLC. Altogether, our study highlights the need for mechanism-guided targeting of anti-apoptotic BCL-2 proteins to effectively activate the mitochondrial cell death programme to kill cancer cells.</jats:p