977 research outputs found
Developing an Adeno-Associated Viral Vector (AAV) Toolbox for CNS Gene Therapy: A Dissertation
Neurological disorders – disorders of the brain, spine and associated nerves – are a leading contributor to global disease burden with a sizable economic cost. Adeno-associated viral (AAV) vectors have emerged as an effective platform for CNS gene therapy and have shown early promise in clinical trials. These trials involve direct infusion into brain parenchyma, an approach that may be suboptimal for treatment of neurodegenerative disorders, which often involve more than a single structure in the CNS. However, overall neuronal transduction efficiency of vectors derived from naturally occurring AAV capsids after systemic administration is relatively low. We have developed novel capsids AAV-AS and AAV-B1 that lead to widespread gene delivery throughout the brain and spinal cord, particularly to neuronal populations. Both transduce the adult mouse brain \u3e10-fold more efficiently than the clinical gold standard AAV9 upon intravascular infusion, with gene transfer to multiple neuronal sub-populations. These vectors are also capable of neuronal transduction in a normal cat. We have demonstrated the efficacy of AAV-AS in the context of Huntington\u27s disease by knocking down huntingtin mRNA 33-50% after a single intravenous injection, which is better than what can be achieved by AAV9 at the particular dose. AAVB1 additionally transduces muscle, beta cells, pulmonary alveoli and retinal vasculature at high efficiency, and has reduced sensitivity to neutralizing antibodies in human sera. Generation of this vector toolbox represents a major step towards gaining genetic access to the entire CNS, and provides a platform to develop new gene therapies for neurodegenerative disorders
Reionization constraints using Principal Component Analysis
Using a semi-analytical model developed by Choudhury & Ferrara (2005) we
study the observational constraints on reionization via a principal component
analysis (PCA). Assuming that reionization at z>6 is primarily driven by
stellar sources, we decompose the unknown function N_{ion}(z), representing the
number of photons in the IGM per baryon in collapsed objects, into its
principal components and constrain the latter using the photoionization rate
obtained from Ly-alpha forest Gunn-Peterson optical depth, the WMAP7 electron
scattering optical depth and the redshift distribution of Lyman-limit systems
at z \sim 3.5. The main findings of our analysis are: (i) It is sufficient to
model N_{ion}(z) over the redshift range 2<z<14 using 5 parameters to extract
the maximum information contained within the data. (ii) All quantities related
to reionization can be severely constrained for z<6 because of a large number
of data points whereas constraints at z>6 are relatively loose. (iii) The weak
constraints on N_{ion}(z) at z>6 do not allow to disentangle different feedback
models with present data. There is a clear indication that N_{ion}(z) must
increase at z>6, thus ruling out reionization by a single stellar population
with non-evolving IMF, and/or star-forming efficiency, and/or photon escape
fraction. The data allows for non-monotonic N_{ion}(z) which may contain sharp
features around z \sim 7. (iv) The PCA implies that reionization must be 99%
completed between 5.8<z<10.3 (95% confidence level) and is expected to be 50%
complete at z \approx 9.5-12. With future data sets, like those obtained by
Planck, the z>6 constraints will be significantly improved.Comment: Accepted in MNRAS. Revised to match the accepted versio
Dark matter, extra-terrestrial gamma-rays and the MSSM: a viability study
We fit the -ray excess from the galactic centre (GC) in terms of
parameters of the minimal supersymmetric standard model (MSSM). Consistency
with other -ray observation, such as those from dwarf spheroidal
galaxies, is also ensured, in addition to the constraints from direct dark
matter search. Furthermore, we expect the contribution to the relic density
from the MSSM dark mater candidate, namely, the lightest neutralino, should not
go below the stipulated value; otherwise it will amount to going beyond the
MSSM by including some additional dark matter source. After a detailed scan of
the parameter space in terms of four representative types of particle spectra,
we identify the ones that are best fit to the observed data. However, these two
are somewhat unsatisfactory in terms of as well as -values.
In some case(s), the unacceptability of low- regions due to
direct search constraint is responsible for this. In others, the observed shape
of the -ray spectrum makes the fits unsatisfactory. The imposed lower
limit on relic density, too, has a role to play all along. On the whole, the
conclusion is that the MSSM is not a very satisfactory fit for the GC
-ray compounded with other cosmological observations and direct search
limits.Comment: 40 pages, 16 figures: figures corrected, typos corrected, matches
with version published in JCA
Heavy dark matter particle annihilation in dwarf spheroidal galaxies: radio signals at the SKA telescope
A weakly interacting dark matter candidate is very difficult to detect at
high-energy colliders like the LHC, if its mass is close to, or higher than, a
TeV. We argue that the pair-annihilation of such particles may give rise to
-pairs in dwarf spheroidal galaxies (dSph), which in turn can lead to
radio synchrotron signals that are detectable at the upcoming square kilometre
array (SKA) telescope within a fairly moderate observation time. We investigate
in detail the underlying mechanisms that make this possible. Both particle
physics issues and those pertaining to astrophysics, such as diffusion,
electromagnetic energy loss and the effects of interstellar magnetic field, are
examined with reference to their roles in generating radio flux. We first
identify the detectability criteria in a model-independent manner. It is
observed that fluxes may be detectable for scenarios that are consistent with
all constraints available till date from -ray and cosmic-ray
observations. Thereafter, using benchmarks based on popular scenarios involving
physics beyond the standard model, we show that it should be possible to detect
the radio flux from a dSph like Draco with 100 hours of observation at the SKA,
for dark matter particle masses upto 4-8 TeV. The corresponding frequency
distributions are also presented, where it is found that the frequency range
300 MHz - 50 GHz is especially useful for recording the annihilation signals of
trans-TeV particles.Comment: 27 pages, 14 figure
ANTIOXIDANT AND CYTOTOXIC ACTIVITIES OF ARECA CATECHU SEED EXTRACT IN SWISS ALBINO MICE USING EAC CELL LINE IN DIFFERENT CULTURE MEDIUM
Objective: Areca nut is the dried ripe seeds of Areca catechu, belonging to family Palmae. Areca nut contains a number of alkaloids, belonging to pyridine and piperidine groups, derived from amino acid lysine. Arecoline a nicotinic acid-based alkaloid present which exerts sialagogue property. But the habit of chewing marketed gutka may cause oral leukoplakia, sometimes lead to squamous cell carcinoma. However, Based on the phytochemical compounds present, it is predicted that it must show antioxidant and may show cytotoxic activities.
Methods: The antioxidant activity (nitrite scavenging and hydrogen peroxide scavenging) and cytotoxic activity in two different medium were checked in EAC cell line using the swiss albino mice model.
Results: The study was also postulated an idea about the qualitative and quantitive analysis of Areca catechu. The plant extract showed good Nitrite and Hydrogen peroxide scavenging activity. The cytotoxicity study conducted in swiss albino mice, cell viability and IC50 value was checked. The cytotoxic activity of different concentrations of different fractions of plant extract was checked in two different medium, i.e., PBS and RPMI 1640. IC50 values for following fractions which were studied in PBS; as, 91.73±73 (µg/ml), 183±36.24 (µg/ml), 53.74±1.562 (µg/ml) for crude ethanolic extract, alkaloid fraction and flavonoid fraction respectively. IC50 value in RPMI 1640 medium obtained as; 44.18±1.09µg/ml, 54.27±0.2279µg/ml and 51.24±2.461µg/ml for crude ethanolic extract, Alkaloid and Flavonoid fraction, respectively.
Conclusion: Areca nut extract showed good scavenging activity depending on concentration. Relatively RPMI 1640 medium showed better cytotoxic activity than other mediums
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