4-(3-Carb­oxy-1-ethyl-6-fluoro-4-oxo-1,4-dihydro-7-quinol­yl)-1-methyl­piper­azin­ium picrate

The pefloxacinium cation of the title salt, C17H21FN3O3 +·C6H2N3O7 −, is composed of an essentially planar quinoline ring system [maximum deviation = 0.021 (2) Å] and a piperazine ring, which adopts a chair conformation. In the picrate anion, the two O atoms of one of the o-NO2 groups are disordered over two positions, with an occupancy ratio of 0.56 (4):0.44 (4). In the crystal structure, cations and anions are connected by inter­molecular N—H⋯O, O—H⋯O, C—H⋯O and C—H⋯F hydrogen bonds, forming a three-dimensional network. In addition, π–π inter­actions between the pyridine rings and between the benzene rings of the anions, with centroid–centroid distances of 3.6103 (12) and 3.5298 (11) Å, respectively, are observed

Genetic and pharmacological targeting of transcriptional repression in resistance to thyroid hormone alpha

Background Thyroid hormones act in bone and cartilage via thyroid hormone receptor α (TRα). In the absence of T3, TRα interacts with co-repressors, including nuclear receptor co-repressor-1 (NCoR1), which recruit histone deacetylases (HDACs) and mediate transcriptional repression. Dominant-negative mutations of TRα cause resistance to thyroid hormone α (RTHα; OMIM 614450), characterized by excessive repression of T3 target genes leading to delayed skeletal development, growth retardation and bone dysplasia. Treatment with thyroxine has been of limited benefit even in mildly affected individuals and there is a need for new therapeutic strategies. We hypothesized that (i) the skeletal manifestations of RTHα are mediated by the persistent TRα/NCoR1/HDAC repressor complex containing mutant TRα, and (ii) treatment with the HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) would ameliorate these manifestations. Methods We determined the skeletal phenotypes of (i) Thra1PV/+ mice, a well characterized model of RTHα, (ii) Ncor1ΔID/ΔID mice, which express an NCoR1 mutant that fails to interact with TRα, and (iii) Thra1PV/+Ncor1ΔID/ΔID double mutant adult mice. Wild-type, Thra1PV/+, Ncor1ΔID/ΔID, and Thra1PV/+Ncor1ΔID/ΔID double mutant mice were also treated with SAHA to determine whether HDAC inhibition results in amelioration of skeletal abnormalities. Results Thra1PV/+ mice had a severe skeletal dysplasia characterized by short stature, abnormal bone morphology and increased bone mineral content. Despite normal bone length, Ncor1ΔID/ΔID mice displayed increased cortical bone mass, mineralization and strength. Thra1PV/+Ncor1ΔID/ΔID double mutant mice displayed only a small improvement of skeletal abnormalities compared to Thra1PV/+ mice. Treatment with SAHA to inhibit histone deacetylation had no beneficial or detrimental effects on bone structure, mineralization or strength in wild-type or mutant mice. Conclusions These studies indicate treatment with SAHA is unlikely to improve the skeletal manifestations of RTHα. Nevertheless, the findings (i) confirm that TRα1 has a critical role in the regulation of skeletal development and adult bone mass, (ii) suggest a physiological role for alternative co-repressors that interact with TR in skeletal cells, and (iii) demonstrate a novel role for NCoR1 in the regulation of adult bone mass and strength

Impaired spatial memory and enhanced long-term potentiation in mice with forebrain-specific ablation of the Stim genes

Recent findings point to a central role of the endoplasmic reticulum-resident STIM (Stromal Interaction Molecule) proteins in shaping the structure and function of excitatory synapses in the mammalian brain. The impact of the Stim genes on cognitive functions remains, however, poorly understood. To explore the function of the Stim genes in learning and memory, we generated three mouse strains with conditional deletion (cKO) of Stim1 and/or Stim2 in the forebrain. Stim1, Stim2, and double Stim1/Stim2 cKO mice show no obvious brain structural defects or locomotor impairment. Analysis of spatial reference memory in the Morris water maze revealed a mild learning delay in Stim1 cKO mice, while learning and memory in Stim2 cKO mice was indistinguishable from their control littermates. Deletion of both Stim genes in the forebrain resulted, however, in a pronounced impairment in spatial learning and memory reflecting a synergistic effect of the Stim genes on the underlying neural circuits. Notably, long-term potentiation (LTP) at CA3-CA1 hippocampal synapses was markedly enhanced in Stim1/Stim2 cKO mice and was associated with increased phosphorylation of the AMPA receptor subunit GluA1, the transcriptional regulator CREB and the L-type Voltage-dependent Ca(2+) channel Cav1.2 on protein kinase A (PKA) sites. We conclude that STIM1 and STIM2 are key regulators of PKA signaling and synaptic plasticity in neural circuits encoding spatial memory. Our findings also reveal an inverse correlation between LTP and spatial learning/memory and suggest that abnormal enhancement of cAMP/PKA signaling and synaptic efficacy disrupts the formation of new memories

Neutron-proton bremsstrahlung from intermediate energy heavy-ion reactions as a probe of the nuclear symmetry energy?

Hard photons from neutron-proton bremsstrahlung in intermediate energy heavy-ion reactions are examined as a potential probe of the nuclear symmetry energy within a transport model. Effects of the symmetry energy on the yields and spectra of hard photons are found to be generally smaller than those due to the currently existing uncertainties of both the in-medium nucleon-nucleon cross sections and the photon production probability in the elementary process $pn\to pn\gamma$. Very interestingly, nevertheless, the ratio of hard photon spectra $R_{1/2}(\gamma)$ from two reactions using isotopes of the same element is not only approximately independent of these uncertainties but also quite sensitive to the symmetry energy. For the head-on reactions of $^{132}Sn+^{124}Sn$ and $^{112}Sn+^{112}Sn$ at $E_{beam}/A=50$ MeV, for example, the $R_{1/2}(\gamma)$ displays a rise up to 15% when the symmetry energy is reduced by about 20% at $\rho=1.3\rho_0$ which is the maximum density reached in these reactions.Comment: Added new results in Fig. 6 and new references [27.28]. Phys. Lett. B in pres

Chromatographically isolated CD63+CD81+ extracellular vesicles from mesenchymal stromal cells rescue cognitive impairments after TBI

Extracellular vesicles (EVs) secreted by cells present an attractive strategy for developing new therapies, but progress in the field is limited by several issues: The quality of the EVs varies with the type and physiological status of the producer cells; protocols used to isolate the EVs are difficult to scale up; and assays for efficacy are difficult to develop. In the present report, we have addressed these issues by using human mesenchymal stem/stromal cells (MSCs) that produce EVs when incubated in a protein-free medium, preselecting the preparations of MSCs with a biomarker for their potency in modulating inflammation, incubating the cells in a chemically defined protein-free medium that provided a stable environment, isolating the EVs with a scalable chromatographic procedure, and developing an in vivo assay for efficacy of the cells in suppressing neuroinflammation after traumatic brain injury (TBI) in mice. In addition, we demonstrate that i.v. infusion of the isolated EVs shortly after induction of TBI rescued pattern separation and spatial learning impairments 1 mo later

Upper limits on the observational effects of nuclear pasta in neutron stars

The effects of the existence of exotic nuclear shapes at the bottom of the neutron star inner crust - nuclear `pasta' - on observational phenomena are estimated by comparing the limiting cases that those phases have a vanishing shear modulus and that they have the shear modulus of a crystalline solid . We estimate the effect on torsional crustal vibrations and on the maximum quadrupole ellipticity sustainable by the crust. The crust composition and transition densities are calculated consistently with the global properties, using a liquid drop model with a bulk nuclear equation of state (EoS) which allows a systematic variation of the nuclear symmetry energy. The symmetry energy J and its density dependence L at nuclear saturation density are the dominant nuclear inputs which determine the thickness of the crust, the range of densities at which pasta might appear, as well as global properties such as the radius and moment of inertia. We show the importance of calculating the global neutron star properties on the same footing as the crust EoS, and demonstrate that in the range of experimentally acceptable values of L, the pasta phase can alter the crust frequencies by up to a factor of three, exceeding the effects of superfluidity on the crust modes, and decrease the maximum quadrupole ellipticity sustainable by the crust by up to an order of magnitude. The signature of the pasta phases and the density dependence of the symmetry energy on the potential observables highlights the possibility of constraining the EoS of dense, neutron-rich matter and the properties of the pasta phases using astrophysical observations.Comment: 8 pages, 7 figures, accepted for publication in Monthly Notices of the Royal Astronomical Societ

A survey of the parameter space of the compressible liquid drop model as applied to the neutron star inner crust

We present a systematic survey the range of predictions of the neutron star inner crust composition, crust-core transition densities and pressures, and density range of the nuclear `pasta' phases at the bottom of the crust provided by the compressible liquid drop model in the light of current experimental and theoretical constraints on model parameters. Using a Skyrme-like model for nuclear matter, we construct baseline sequences of crust models by consistently varying the density dependence of the bulk symmetry energy at nuclear saturation density, $L$, under two conditions: (i) that the magnitude of the symmetry energy at saturation density $J$ is held constant, and (ii) $J$ correlates with $L$ under the constraint that the pure neutron matter (PNM) EoS satisfies the results of ab-initio calculations at low densities. Such baseline crust models facilitate consistent exploration of the $L$ dependence of crustal properties. The remaining surface energy and symmetric nuclear matter parameters are systematically varied around the baseline, and different functional forms of the PNM EoS at sub-saturation densities implemented, to estimate theoretical `error bars' for the baseline predictions. Inner crust composition and transition densities are shown to be most sensitive to the surface energy at very low proton fractions and to the behavior of the sub-saturation PNM EoS. Recent calculations of the energies of neutron drops suggest that the low-proton-fraction surface energy might be higher than predicted in Skyrme-like models, which our study suggests may result in a greatly reduced volume of pasta in the crust than conventionally predicted.Comment: 37 Pages, 16 figures, accepted for publication in Astrophysical Journal Supplement Serie

Nuclear limits on gravitational waves from elliptically deformed pulsars

Gravitational radiation is a fundamental prediction of General Relativity. Elliptically deformed pulsars are among the possible sources emitting gravitational waves (GWs) with a strain-amplitude dependent upon the star's quadrupole moment, rotational frequency, and distance from the detector. We show that the gravitational wave strain amplitude $h_0$ depends strongly on the equation of state of neutron-rich stellar matter. Applying an equation of state with symmetry energy constrained by recent nuclear laboratory data, we set an upper limit on the strain-amplitude of GWs produced by elliptically deformed pulsars. Depending on details of the EOS, for several millisecond pulsars at distances $0.18kpc$ to $0.35kpc$ from Earth, the {\it maximal} $h_0$ is found to be in the range of $\sim[0.4-1.5]\times 10^{-24}$. This prediction serves as the first {\it direct} nuclear constraint on the gravitational radiation. Its implications are discussed.Comment: 13 pages, 5 figures, and 2 Table. Accepted for publication in Physics Letters

Comparison of pulmonary and extrapulmonary tuberculosis in Nepal- a hospital-based retrospective study

<p>Abstract</p> <p>Background</p> <p>Studies from developed countries have reported on host-related risk factors for extra-pulmonary tuberculosis (EPTB). However, similar studies from high-burden countries like Nepal are lacking. Therefore, we carried out this study to compare demographic, life-style and clinical characteristics between EPTB and PTB patients.</p> <p>Methods</p> <p>A retrospective analysis was carried out on 474 Tuberculosis (TB) patients diagnosed in a tertiary care hospital in western Nepal. Characteristics of demography, life-style and clinical features were obtained from medical case records. Risk factors for being an EPTB patient relative to a PTB patient were identified using logistic regression analysis.</p> <p>Results</p> <p>The age distribution of the TB patients had a bimodal distribution. The male to female ratio for PTB was 2.29. EPTB was more common at younger ages (< 25 years) and in females. Common sites for EPTB were lymph nodes (42.6%) and peritoneum and/or intestines (14.8%). By logistic regression analysis, age less than 25 years (OR 2.11 95% CI 1.12–3.68) and female gender (OR 1.69, 95% CI 1.12–2.56) were associated with EPTB. Smoking, use of immunosuppressive drugs/steroids, diabetes and past history of TB were more likely to be associated with PTB.</p> <p>Conclusion</p> <p>Results suggest that younger age and female gender may be independent risk factors for EPTB in a high-burden country like Nepal. TB control programmes may target young and female populations for EPTB case-finding. Further studies are necessary in other high-burden countries to confirm our findings.</p

STIM2 regulates AMPA receptor trafficking and plasticity at hippocampal synapses

STIM2 is an integral membrane protein of the endoplasmic reticulum (ER) that regulates the activity of plasma membrane (PM) channels at ER-PM contact sites. Recent studies show that STIM2 promotes spine maturation and surface expression of the AMPA receptor (AMPAR) subunit GluA1, hinting at a probable role in synaptic plasticity. Here, we used a Stim2 cKO mouse to explore the function of STIM2 in Long-Term Potentiation (LTP) and Depression (LTD), two widely-studied models of synaptic plasticity implicated in information storage. We found that STIM2 is required for the stable expression of both LTP and LTD at CA3-CA1 hippocampal synapses. Altered plasticity in Stim2 cKO mice is associated with subtle alterations in the shape and density of dendritic spines in CA1 neurons. Further, surface delivery of GluA1 in response to LTP-inducing chemical manipulations was markedly reduced in excitatory neurons derived from Stim2 cKO mice. GluA1 endocytosis following chemically-induced LTD was also impaired in Stim2 cKO neurons. We conclude that STIM2 facilitates synaptic delivery and removal of AMPARs and regulates activity-dependent changes in synaptic strength through a unique mode of communication between the ER and the synapse