294 research outputs found
Antinociceptive effects of morphine and naloxone in mu-opioid receptor knockout mice transfected with the MORS196A gene
<p>Abstract</p> <p>Background</p> <p>Opioid analgesics such as morphine and meperidine have been used to control moderate to severe pain for many years. However, these opioids have many side effects, including the development of tolerance and dependence after long-term use, which has limited their clinical use. We previously reported that mutations in the mu-opioid receptors (MOR) S196L and S196A rendered them responsive to the opioid antagonist naloxone without altering the agonist phenotype. In MORS196A knock-in mice, naloxone and naltrexone were antinociceptive but did not cause tolerance or physical dependence. In this study we delivery this mutated MOR gene into pain related pathway to confirm the possibility of <it>in vivo </it>transfecting MORS196A gene and using naloxone as a new analgesic agent.</p> <p>Methods</p> <p>The MOR-knockout (MOR-KO) mice were used to investigate whether morphine and naloxone could show antinociceptive effects when MORS196A gene was transfected into the spinal cords of MOR-KO mice. Double-stranded adeno-associated virus type 2 (dsAAV2) was used to deliver the MORS196A-enhanced green fluorescence protein (EGFP) gene by microinjected the virus into the spinal cord (S2/S3) dorsal horn region. Tail-flick test was used to measure the antinociceptive effect of drugs.</p> <p>Results</p> <p>Morphine (10 mg/kg, s.c.) and naloxone (10 mg/kg, s.c.) had no antinociceptive effects in MOR-KO mice before gene transfection. However, two or three weeks after the MOR-S196A gene had been injected locally into the spinal cord of MOR-KO mice, significant antinociceptive effects could be induced by naloxone or morphine. On the other hand, only morphine but not naloxone induced significant tolerance after sub-chronic treatment.</p> <p>Conclusion</p> <p>Transfecting the MORS196A gene into the spinal cord and systemically administering naloxone in MOR-KO mice activated the exogenously delivered mutant MOR and provided antinociceptive effect without causing tolerance. Since naloxone will not activate natural MOR in normal animals or humans, it is expected to produce fewer side effects and less tolerance and dependence than traditional opioid agonists do.</p
Thermoelectric transport properties of CaMg2Bi2, EuMg2Bi2, and YbMg2Bi2
The thermoelectric transport properties of CaMg2Bi2, EuMg2Bi2, and YbMg2Bi2
were characterized between 2 and 650K. As synthesized, the polycrystalline
samples are found to have lower p-type carrier concentrations than
single-crystalline samples of the same empirical formula. These low carrier
concentration samples possess the highest mobilities yet reported for materials
with the CaAl2Si2 structure type, with a mobility of ~740cm/V/s observed in
EuMg2Bi2 at 50K. Despite decreases in the Seebeck coefficient (\alpha) and
electrical resistivity (\rho) with increasing temperature, the power factor
(\alpha^2/\rho) increases for all temperatures examined. This behavior suggests
a strong asymmetry in the conduction of electrons and holes. The highest figure
of merit (zT) is observed in YbMg2Bi2, with zT approaching 0.4 at 600K for two
samples with carrier densities of approximately 2x10^{18}cm^{-3} and
8x10^{18}cm^{-3} at room temperature. Refinements of neutron powder diffraction
data yield similar behavior for the structures of CaMg2Bi2 and YbMg2Bi2, with
smooth lattice expansion and relative expansion in being ~35% larger than
relative expansion in at 973K. First principles calculations reveal an
increasing band gap as Bi is replaced by Sb then As, and subsequent Boltzmann
transport calculations predict an increase in \alpha for a given associated
with an increased effective mass as the gap opens. The magnitude and
temperature dependence of \alpha suggests higher zT is likely to be achieved at
larger carrier concentrations, roughly an order of magnitude higher than those
in the current polycrystalline samples, which is also expected from the
detailed calculations
Observation of the nonlinear Hall effect under time reversal symmetric conditions
The electrical Hall effect is the production of a transverse voltage under an
out-of-plane magnetic field. Historically, studies of the Hall effect have led
to major breakthroughs including the discoveries of Berry curvature and the
topological Chern invariants. In magnets, the internal magnetization allows
Hall conductivity in the absence of external magnetic field. This anomalous
Hall effect (AHE) has become an important tool to study quantum magnets. In
nonmagnetic materials without external magnetic fields, the electrical Hall
effect is rarely explored because of the constraint by time-reversal symmetry.
However, strictly speaking, only the Hall effect in the linear response regime,
i.e., the Hall voltage linearly proportional to the external electric field,
identically vanishes due to time-reversal symmetry. The Hall effect in the
nonlinear response regime, on the other hand, may not be subject to such
symmetry constraints. Here, we report the observation of the nonlinear Hall
effect (NLHE) in the electrical transport of the nonmagnetic 2D quantum
material, bilayer WTe2. Specifically, flowing an electrical current in bilayer
WTe2 leads to a nonlinear Hall voltage in the absence of magnetic field. The
NLHE exhibits unusual properties sharply distinct from the AHE in metals: The
NLHE shows a quadratic I-V characteristic; It strongly dominates the nonlinear
longitudinal response, leading to a Hall angle of about 90 degree. We further
show that the NLHE directly measures the "dipole moment" of the Berry
curvature, which arises from layer-polarized Dirac fermions in bilayer WTe2.
Our results demonstrate a new Hall effect and provide a powerful methodology to
detect Berry curvature in a wide range of nonmagnetic quantum materials in an
energy-resolved way
Thermal infrared emission reveals the Dirac point movement in biased graphene
Graphene is a 2-dimensional material with high carrier mobility and thermal
conductivity, suitable for high-speed electronics. Conduction and valence bands
touch at the Dirac point. The absorptivity of single-layer graphene is 2.3%,
nearly independent of wavelength. Here we investigate the thermal radiation
from biased graphene transistors. We find that the emission spectrum of
single-layer graphene follows that of a grey body with constant emissivity (1.6
\pm 0.8)%. Most importantly, we can extract the temperature distribution in the
ambipolar graphene channel, as confirmed by Stokes/anti-Stokes measurements.
The biased graphene exhibits a temperature maximum whose location can be
controlled by the gate voltage. We show that this peak in temperature reveals
the spatial location of the minimum in carrier density, i.e. the Dirac point.Comment: Accepted in principle at Nature Nanotechnolog
Intratumoral Decorin Gene Delivery by AAV Vector Inhibits Brain Glioblastomas and Prolongs Survival of Animals by Inducing Cell Differentiation
Glioblastoma multiforme (GBM) is the most malignant cancer in the central nervous system with poor clinical prognosis. In this study, we investigated the therapeutic effect of an anti-cancer protein, decorin, by delivering it into a xenograft U87MG glioma tumor in the brain of nude mice through an adeno-associated viral (AAV2) gene delivery system. Decorin expression from the AAV vector in vitro inhibited cultured U87MG cell growth by induction of cell differentiation. Intracranial injection of AAV-decorin vector to the glioma-bearing nude mice in vivo significantly suppressed brain tumor growth and prolonged survival when compared to control non-treated mice bearing the same U87MG tumors. Proteomics analysis on protein expression profiles in the U87MG glioma cells after AAV-mediated decorin gene transfer revealed up- and down-regulation of important proteins. Differentially expressed proteins between control and AAV-decorin-transduced cells were identified through MALDI-TOF MS and database mining. We found that a number of important proteins that are involved in apoptosis, transcription, chemotherapy resistance, mitosis, and fatty acid metabolism have been altered as a result of decorin overexpression. These findings offer valuable insight into the mechanisms of the anti-glioblastoma effects of decorin. In addition, AAV-mediated decorin gene delivery warrants further investigation as a potential therapeutic approach for brain tumors
Chitosan Modification of Adenovirus to Modify Transfection Efficiency in Bovine Corneal Epithelial Cells
BACKGROUND: The purpose of this study is to modulate the transfection efficiency of adenovirus (Ad) on the cornea by the covalent attachment of chitosan on adenoviral capsids via a thioether linkage between chitosan modified with 2-iminothiolane and Ad cross-linked with N-[gamma-maleimidobutyryloxy]succinimide ester (GMBS). METHODOLOGY/PRINCIPAL FINDINGS: Modified Ad was obtained by reaction with the heterobifunctional crosslinking reagent, GMBS, producing maleimide-modified Ad (Ad-GMBS). Then, the chitosan-SH was conjugated to Ad-GMBS via a thioether bond at different ratios of Ad to GMBS to chitosan-SH. The sizes and zeta potentials of unmodified Ad and chitosan-modified Ads were measured, and the morphologies of the virus particles were observed under transmission electron microscope. Primary cultures of bovine corneal epithelial cells were transfected with Ads and chitosan-modified Ads in the absence or presence of anti-adenovirus antibodies. Chitosan modification did not significantly change the particle size of Ad, but the surface charge of Ad increased significantly from -24.3 mV to nearly neutral. Furthermore, primary cultures of bovine corneal epithelial cells were transfected with Ad or chitosan-modified Ad in the absence or presence of anti-Ad antibodies. The transfection efficiency was attenuated gradually with increasing amounts of GMBS. However, incorporation of chitosan partly restored transfection activity and rendered the modified antibody resistant to antibody neutralization. CONCLUSIONS/SIGNIFICANCE: Chitosan can provide a platform for chemical modification of Ad, which offers potential for further in vivo applications
The association between subjective memory complaint and objective cognitive function in older people with previous major depression
The goal of this study is to investigate associations between subjective memory complaint and objective cognitive performance in older people with previous major depression-a high-risk sample for cognitive impairment and later dementia. A cross-sectional study was carried out in people aged 60 or over with previous major depression but not fulfilling current major depression criteria according to DSM-IV-TR. People with dementia or Mini-Mental State Examination score less than 17 were excluded. Subjective memory complaint was defined on the basis of a score โง4 on the subscale of Geriatric Mental State schedule, a maximum score of 8. Older people aged equal or over 60 without any psychiatric diagnosis were enrolled as healthy controls. Cognitive function was evaluated using a series of cognitive tests assessing verbal memory, attention/speed, visuospatial function, verbal fluency, and cognitive flexibility in all participants. One hundred and thirteen older people with previous major depression and forty-six healthy controls were enrolled. Subjective memory complaint was present in more than half of the participants with depression history (55.8%). Among those with major depression history, subjective memory complaint was associated with lower total immediate recall and delayed verbal recall scores after adjustment. The associations between subjective memory complaint and worse memory performance were stronger in participants with lower depressive symptoms (Hamilton Depression Rating Scale score<7). The results suggest subjective memory complaint may be a valid appraisal of memory performance in older people with previous major depression and consideration should be given to more proactive assessment and follow-up in these clinical samples
Sublethal Doses of Anthrax Lethal Toxin on the Suppression of Macrophage Phagocytosis
BACKGROUND: Lethal toxin (LT), the major virulence factor produced by Bacillus anthracis, has been shown to suppress the immune system, which is beneficial to the establishment of B. anthracis infections. It has been suggested that the suppression of MEK/MAPK signaling pathways of leukocytes contributes to LT-mediated immunosuppressive effects. However, the involvement of MAPK independent pathways has not been clearly elucidated; nor has the crucial role played by LT in the early stages of infection. Determining whether LT exerts any pathological effects before being enriched to an MEK inhibitory level is an important next step in the furtherance of this field. METHODOLOGY/PRINCIPAL FINDINGS: Using a cell culture model, we determined that low doses of LT inhibited phagocytosis of macrophages, without influencing MAPK pathways. Consistent low doses of LT significantly suppressed bacterial clearance and enhanced the mortality of mice with bacteremia, without suppressing the MEK1 of splenic and peripheral blood mononuclear cells. CONCLUSION/SIGNIFICANCE: These results suggest that LT suppresses the phagocytes in a dose range lower than that required to suppress MEK1 in the early stages of infection
- โฆ