Efficacy and tolerability of the Galanin Analog NAX 5055 in the multiple-hit rat model of symptomatic infantile spasms

Infantile spasms are seizures manifesting in infantile epileptic encephalopathies that are associated with poor epilepsy and cognitive outcomes. The current therapies are not always effective or are associated with serious side effects. Early cessation of spasms has been proposed to improve long-term outcomes. To identify new therapies for infantile spasms with rapid suppression of spasms, we are using the multiple-hit rat model of infantile spasms, which is a model of refractory infantile spasms. Here, we are testing the efficacy and tolerability of a single dose of the galanin receptor 1 preferring analog, NAX 5055, in the multiple-hit model of spasms. To induce the model, postnatal day 3 (PN3) male Sprague-Dawley rats underwent right intracerebral infusions of doxorubicin and lipopolysaccharide; p-chlorophenylalanine was then injected intraperitoneally (i.p.) at PN5. After the onset of spasms at PN4, 11-14 rats/group were injected i.p. with either NAX 5055 (0.5, 1, 2, or 4mg/kg) or vehicle. Video monitoring for spasms included a 1h pre-injection period, followed by 5h of recording post-injection, and two 2h sessions on PN5. The study was conducted in a randomized, blinded manner. Neurodevelopmental reflexes were assessed daily as well as at 2h after injection. Respiratory function, heart rate, pulse distension, oximetry and blood glucose were measured 4h after injection. The relative expression of GalR1 and GalR2 mRNA over β-actin in the cerebral cortex and hippocampus was determined with real time reverse transcription polymerase chain reaction. There was no acute effect of NAX 5055 on spasm frequency after the single dose of NAX 5055 (n=11-13 rats/group, following exclusions). Neurodevelopmental reflexes, vital signs, blood glucose measured 4h post-injection, and survival were not affected. A reduction in pulse and breath distention of unclear clinical significance was observed with the 7mg/kg NAX 5055 dose. GalR1 mRNA was present in the cerebral cortex and hippocampus of PN4 and adult rats. The hippocampal - but not the cortical - GalR1 mRNA expression was significantly lower in PN4 pups than in adults. GalR1 mRNA was also at least 20 times less abundant in the PN4 cortex than GalR2 mRNA. In conclusion, a single dose of NAX 5055 has no acute efficacy on spasms or toxicity in the multiple hit rat model of medically refractory infantile spasms. Our findings cannot exclude the possibility that repetitive NAX 5055 administration may show efficacy on spasms. The higher expression of GalR2 in the PN4 cortex suggests that GalR2-preferring analogs may be of interest to test for efficacy on spasms

Hawking Radiation as Quantum Tunneling in Rindler Coordinate

We substantiate the Hawking radiation as quantum tunneling of fields or particles crossing the horizon by using the Rindler coordinate. The thermal spectrum detected by an accelerated particle is interpreted as quantum tunneling in the Rindler spacetime. Representing the spacetime near the horizon locally as a Rindler spacetime, we find the emission rate by tunneling, which is expressed as a contour integral and gives the correct Boltzmann factor. We apply the method to non-extremal black holes such as a Schwarzschild black hole, a non-extremal Reissner-Nordstr\"{o}m black hole, a charged Kerr black hole, de Sitter space, and a Schwarzschild-anti de Sitter black hole.Comment: LaTex 19 pages, no figure; references added and replaced by the version accepted in JHE

Glass Transition of Hard Sphere Systems: Molecular Dynamics and Density Functional Theory

The glass transition of a hard sphere system is investigated within the framework of the density functional theory (DFT). Molecular dynamics (MD) simulations are performed to study dynamical behavior of the system on the one hand and to provide the data to produce the density field for the DFT on the other hand. Energy landscape analysis based on the DFT shows that there appears a metastable (local) free energy minimum representing an amorphous state as the density is increased. This state turns out to become stable, compared with the uniform liquid, at some density, around which we also observe sharp slowing down of the $alpha$ relaxation in MD simulations.Comment: 5 pages, 5 figure

Graft immaturity and safety concerns in transplanted human kidney organoids

For chronic kidney disease, regeneration of lost nephrons with human kidney organoids derived from induced pluripotent stem (iPS) cells is proposed to be an attractive potential therapeutic option. It remains unclear, however, whether organoids transplanted into kidneys in vivo would be safe or functional. Here, we purified kidney organoids and transplanted them beneath the kidney capsules of immunodeficient mice to test their safety and maturity. Kidney organoid grafts survived for months after transplantation and became vascularized from host mouse endothelial cells. Nephron-like structures in grafts appeared more mature than kidney organoids in vitro, but remained immature compared with the neighboring mouse kidney tissue. Ultrastructural analysis revealed filtration barrier-like structures, capillary lumens, and tubules with brush border in the transplanted kidney organoids, which were more mature than those of the kidney organoids in vitro but not as organized as adult mammalian kidneys. Immaturity was a common feature of three separate differentiation protocols by immunofluorescence analysis and single cell RNA sequencing. Stroma of transplanted kidney organoid grafts were filled with vimentin-positive mesenchymal cells, and chondrogenesis, cystogenesis, and stromal expansion were observed in the long term. Transcription profiles showed that long-term maintenance after kidney organoid transplantation induced transcriptomic reprogramming with prominent suppression of cell-cycle-related genes and upregulation of extracellular matrix organization. Our data suggest that kidney organoids derived from iPS cells may be transplantable but strategies to improve nephron differentiation and purity are required before they can be applied in humans as a therapeutic option.11Ysciescopuskc

Low-Loss All-Optical Zeno Switch in a Microdisk Cavity Using EIT

We present theoretical results of a low-loss all-optical switch based on electromagnetically induced transparency and the classical Zeno effect in a microdisk resonator. We show that a control beam can modify the atomic absorption of the evanescent field which suppresses the cavity field buildup and alters the path of a weak signal beam. We predict more than 35 dB of switching contrast with less than 0.1 dB loss using just 2 micro-Watts of control-beam power for signal beams with less than single photon intensities inside the cavity.Comment: Updated with new references, corrected Eq 2a, and added introductory text. 7 pages, 5 figures, 3 table

Neutralino dark matter stars can not exist

Motivated by the recent "Cosmos Project" observation of dark-matter concentrations with no ordinary matter in the same place, we study the question of the existence of compact objects made of pure dark matter. We assume that the dark matter is neutralino, and compare its elastic and annihilation cross sections. We find that the two cross sections are of the same order of magnitude. This result has a straightforward and important consequence that neutralinos comprising a compact object can not achieve thermal equilibrium. To substantiate our arguments, by solving Oppenheimer-Volkoff equation we constructed a model of the star made of pure neutralinos. We explicitly showed that the condition for the thermal equilibrium supported by the Fermi pressure is never fulfilled inside the star. This neutralino state can not be described by the Fermi-Dirac distribution. Thus, a stable neutralino star, which is supported by the Fermi pressure, can not exist. We also estimated that a stable star can not contain more than a few percents of neutralinos, most of the mass must be in the form of the standard model particles.Comment: published in JHE

Regulator constants and the parity conjecture

The p-parity conjecture for twists of elliptic curves relates multiplicities of Artin representations in p-infinity Selmer groups to root numbers. In this paper we prove this conjecture for a class of such twists. For example, if E/Q is semistable at 2 and 3, K/Q is abelian and K^\infty is its maximal pro-p extension, then the p-parity conjecture holds for twists of E by all orthogonal Artin representations of Gal(K^\infty/Q). We also give analogous results when K/Q is non-abelian, the base field is not Q and E is replaced by an abelian variety. The heart of the paper is a study of relations between permutation representations of finite groups, their "regulator constants", and compatibility between local root numbers and local Tamagawa numbers of abelian varieties in such relations.Comment: 50 pages; minor corrections; final version, to appear in Invent. Mat

Morphologies of Sol–Gel Derived Thin Films of ZnO Using Different Precursor Materials and their Nanostructures

We have shown that the morphological features of the sol–gel derived thin films of ZnO depend strongly on the choice of the precursor materials. In particular, we have used zinc nitrate and zinc acetate as the precursor materials. While the films using zinc acetate showed a smoother topography, those prepared by using zinc nitrate exhibited dendritic character. Both types of films were found to be crystalline in nature. The crystallite dimensions were confined to the nanoscale. The crystallite size of the nanograins in the zinc nitrate derived films has been found to be smaller than the films grown by using zinc acetate as the precursor material. Selected area electron diffraction patterns in the case of both the precursor material has shown the presence of different rings corresponding to different planes of hexagonal ZnO crystal structure. The results have been discussed in terms of the fundamental considerations and basic chemistry governing the growth kinetics of these sol–gel derived ZnO films with both the precursor materials

Single Crystal Growth of Ga2(SexTe1-x)3 Semiconductors and Defect Studies via Positron Annihilation Spectroscopy

Small single crystals of Ga2(SexTe1-x)3 semiconductors, for x = 0.1, 0.2, 0.3, were obtained via modified Bridgman growth techniques. High-resolution powder x-ray diffractometry confirms a zincblende cubic structure, with additional satellite peaks observed near the (111) Bragg line. This suggests the presence of ordered vacancy planes along the [111] direction that have been previously observed in Ga2Te3. Defect studies via positron annihilation spectroscopy show an average positron lifetime of ~400 ps in bulk as-grown specimens. Such a large lifetime suggests that the positron annihilation sites in these materials are dominated by defects. Moreover, analyzing the electron momenta via coincidence Doppler broadening measurements suggests a strong presence of large open-volume defects, likely to be vacancy clusters or voids.Comment: 4 pages, 5 figure