278 research outputs found
Regulation of Ovarian Function by the Germ Cell Specific DAZL Gene
The RNA binding protein DAZL (Deleted in Azoospermia) is essential for germ cell
survival and subsequent fertility. The transgenic mouse DAZL model has confirmed
that knockout (KO) females are infertile as a direct consequence of complete
postnatal oocyte ablation. Interestingly, the heterozygous (Het) DAZL females have
increased fertility giving rise to significantly more viable offspring, accompanied by
significantly reduced plasma FSH and increased inhibin B compared to levels
observed in the wildtype (Wt) females. Recent studies to identify putative DAZL
mRNA targets suggest that DAZL may have multiple functions and mRNA targets
throughout germ cell development. However, how this protein functions within the
oocyte and how functional copy number gives rise to increased fertility remains to be
fully elucidated.The studies in this thesis sought to identify putative DAZL mRNA targets in addition
to molecular mechanisms which may be either affected direct or indirectly as a result
of the functional copy number of DAZL (Wt or Het) within the oocyte or follicular
unit. Oocytes from Wt and Het were evaluated for their expression of selected
oocyte genes and comparative analysis suggests that oocyte gene expression is
significantly altered between the genotypes. Genes of interest include Oospl and
Hlfoo, both of which are down-regulated in mRNA expression in Het d21 oocytes
and dlO ovaries compared to the Wt. Furthermore, an in silico bioinformatics
approach was utilised to identify putative DAZL mRNA targets using a consensus
DAZL binding sequence. One candidate target, PDCD4, previously identified as a
tumour suppressor gene was selected for further investigation. Despite PDCD4
mRNA and protein being highly expressed within the ovary, no difference in mRNA
levels between Het and Wt was observed. However, although not ruling out the
possibility of being a DAZL target we now have evidence that PDCD4 can function
within the steroidogenic cells of the corpus luteum in relation to functional luteolysis.
Abstract
Indirect actions of DAZL upon local regulation and response of follicle growth in
culture were evaluated to investigate follicles at the gonadotrophin dependent stage
of growth. Individual follicles from Wt and Het d21 mice were cultured in the
presence of FSH at liu, 0.5iu, O.liu and O.Oliu for a six day period. Final follicle
size/morphology did not differ between genotypes at liu, 0.5iu and O.liu of FSH, but
by d3 at O.Oliu FSH growth o f Wt follicles was significantly (PO.OOl) perturbed
compared to the Het. Despite no difference in final size between liu, 0.5iu, O.liu
FSH treatments, mRNA analysis of individual follicles demonstrated a significant
up-regulation of FSH receptor (P<0.05), aromatase (P<0.05) and inhibin PA (P<0.01)
and a significant down-regulation in inhibin PB (P<0.01) expression in the Het
follicles compared to the Wt, suggesting an increase in follicle maturity, sensitivity
and hence suitability for selection as viable pre-ovulatory follicles. Furthermore,
atresia rates from cultured follicles were significantly lower (P<0.05 (liu, O.liu
FSH); P<0.01(0,01iu FSH)) in the Het compared to the Wt.These studies provide strong evidence that multiple mechanisms within the
oocyte/follicle are directly and indirectly affected as a result of functional copy
number of DAZL. Although direct in vivo targets remain to be identified it is clear
that DAZL protein potentially targets multiple mRNAs at different stages of
development, pre-programming the oocyte to increase the sensitivity of follicle
and/or the functioning within a transcription complex regulating development. In
conclusion, the beneficial consequences of increased fertility in the Het females is
accompanied by a possible acceleration in oocyte and follicle maturation, an
increased sensitivity to FSH in vitro with evidence of advanced stages of growth and,
a reduction in follicle atresia. These differences support the suggestion that DAZL is
having systemic effects on the paracrine communication within the follicle unit
between the oocyte and somatic cells altering regulation and subsequent selection,
and affecting final ovulation rate and litter size
Decreased oocyte DAZL expression in mice results in increased litter size by modulating follicle-stimulating hormone-induced follicular growth
Dexfenfluramine and the oestrogen-metabolizing enzyme CYP1B1 in the development of pulmonary arterial hypertension
<p>Aims: Pulmonary arterial hypertension (PAH) occurs more frequently in women than men. Oestrogen and the oestrogen-metabolising enzyme cytochrome P450 1B1 (CYP1B1) play a role in the development of PAH. Anorectic drugs such as dexfenfluramine (Dfen) have been associated with the development of PAH. Dfen mediates PAH via a serotonergic mechanism and we have shown serotonin to up-regulate expression of CYP1B1 in human pulmonary artery smooth muscle cells (PASMCs). Thus here we assess the role of CYP1B1 in the development of Dfen-induced PAH.</p>
<p>Methods and results: Dfen (5 mg kg−1 day−1 PO for 28 days) increased right ventricular pressure and pulmonary vascular remodelling in female mice only. Mice dosed with Dfen showed increased whole lung expression of CYP1B1 and Dfen-induced PAH was ablated in CYP1B1−/− mice. In line with this, Dfen up-regulated expression of CYP1B1 in PASMCs from PAH patients (PAH-PASMCs) and Dfen-mediated proliferation of PAH-PASMCs was ablated by pharmacological inhibition of CYP1B1. Dfen increased expression of tryptophan hydroxylase 1 (Tph1; the rate-limiting enzyme in the synthesis of serotonin) in PAH-PASMCs and both Dfen-induced proliferation and Dfen-induced up-regulation of CYP1B1 were ablated by inhibition of Tph1. 17β-Oestradiol increased expression of both Tph1 and CYP1B1 in PAH-PASMCs, and Dfen and 17β-oestradiol had synergistic effects on proliferation of PAH-PASMCs. Finally, ovariectomy protected against Dfen-induced PAH in female mice.</p>
<p>Conclusion: CYP1B1 is critical in the development of Dfen-induced PAH in mice in vivo and proliferation of PAH-PASMCs in vitro. CYP1B1 may provide a novel therapeutic target for PAH.</p>
Asteroseismology of the open clusters NGC 6791, NGC 6811, and NGC 6819 from nineteen months of Kepler photometry
We studied solar-like oscillations in 115 red giants in the three open
clusters NGC 6791, NGC 6811, and NGC 6819, based on photometric data covering
more than 19 months with NASA's Kepler space telescope. We present the
asteroseismic diagrams of the asymptotic parameters \delta\nu_02, \delta\nu_01
and \epsilon, which show clear correlation with fundamental stellar parameters
such as mass and radius. When the stellar populations from the clusters are
compared, we see evidence for a difference in mass of the red giant branch
stars, and possibly a difference in structure of the red clump stars, from our
measurements of the small separations \delta\nu_02 and \delta\nu_01. Ensemble
\'{e}chelle diagrams and upper limits to the linewidths of l = 0 modes as a
function of \Delta\nu of the clusters NGC 6791 and NGC 6819 are also shown,
together with the correlation between the l = 0 ridge width and the T_eff of
the stars. Lastly, we distinguish between red giant branch and red clump stars
through the measurement of the period spacing of mixed dipole modes in 53 stars
among all the three clusters to verify the stellar classification from the
color-magnitude diagram. These seismic results also allow us to identify a
number of special cases, including evolved blue stragglers and binaries, as
well as stars in late He-core burning phases, which can be potentially
interesting targets for detailed theoretical modeling.Comment: 30 pages, 15 figures, 1 table, accepted to Ap
Temporal Changes in Ebola Transmission in Sierra Leone and Implications for Control Requirements: a Real-time Modelling Study.
BACKGROUND: Between August and November 2014, the incidence of Ebola virus disease (EVD) rose dramatically in several districts of Sierra Leone. As a result, the number of cases exceeded the capacity of Ebola holding and treatment centres. During December, additional beds were introduced, and incidence declined in many areas. We aimed to measure patterns of transmission in different regions, and evaluate whether bed capacity is now sufficient to meet future demand. METHODS: We used a mathematical model of EVD infection to estimate how the extent of transmission in the nine worst affected districts of Sierra Leone changed between 10th August 2014 and 18th January 2015. Using the model, we forecast the number of cases that could occur until the end of March 2015, and compared bed requirements with expected future capacity. RESULTS: We found that the reproduction number, R, defined as the average number of secondary cases generated by a typical infectious individual, declined between August and December in all districts. We estimated that R was near the crucial control threshold value of 1 in December. We further estimated that bed capacity has lagged behind demand between August and December for most districts, but as a consequence of the decline in transmission, control measures caught up with the epidemic in early 2015. CONCLUSIONS: EVD incidence has exhibited substantial temporal and geographical variation in Sierra Leone, but our results suggest that the epidemic may have now peaked in Sierra Leone, and that current bed capacity appears to be sufficient to keep the epidemic under-control in most districts
Kepler-432: a red giant interacting with one of its two long period giant planets
We report the discovery of Kepler-432b, a giant planet ()
transiting an evolved star with an orbital period of days. Radial velocities (RVs) reveal that
Kepler-432b orbits its parent star with an eccentricity of , which we also measure independently with
asterodensity profiling (AP; ), thereby confirming
the validity of AP on this particular evolved star. The well-determined
planetary properties and unusually large mass also make this planet an
important benchmark for theoretical models of super-Jupiter formation.
Long-term RV monitoring detected the presence of a non-transiting outer planet
(Kepler-432c; days), and adaptive optics imaging revealed a nearby
(0\farcs87), faint companion (Kepler-432B) that is a physically bound M dwarf.
The host star exhibits high signal-to-noise asteroseismic oscillations, which
enable precise measurements of the stellar mass, radius and age. Analysis of
the rotational splitting of the oscillation modes additionally reveals the
stellar spin axis to be nearly edge-on, which suggests that the stellar spin is
likely well-aligned with the orbit of the transiting planet. Despite its long
period, the obliquity of the 52.5-day orbit may have been shaped by star-planet
interaction in a manner similar to hot Jupiter systems, and we present
observational and theoretical evidence to support this scenario. Finally, as a
short-period outlier among giant planets orbiting giant stars, study of
Kepler-432b may help explain the distribution of massive planets orbiting giant
stars interior to 1 AU.Comment: 22 pages, 19 figures, 5 tables. Accepted to ApJ on Jan 24, 2015
(submitted Nov 11, 2014). Updated with minor changes to match published
versio
Solving the mode identification problem in asteroseismology of F stars observed with Kepler
Asteroseismology of F-type stars has been hindered by an ambiguity in
identification of their oscillation modes. The regular mode pattern that makes
this task trivial in cooler stars is masked by increased linewidths. The
absolute mode frequencies, encapsulated in the asteroseismic variable epsilon,
can help solve this impasse because the values of epsilon implied by the two
possible mode identifications are distinct. We find that the correct epsilon
can be deduced from the effective temperature and the linewidths and we apply
these methods to a sample of solar-like oscillators observed with Kepler.Comment: 7 pages, 4 figures, 1 table, accepted for publication in The
Astrophysical Journal Letter
An asteroseismic membership study of the red giants in three open clusters observed by Kepler: NGC6791, NGC6819, and NGC6811
Studying star clusters offers significant advances in stellar astrophysics
due to the combined power of having many stars with essentially the same
distance, age, and initial composition. This makes clusters excellent test
benches for verification of stellar evolution theory. To fully exploit this
potential, it is vital that the star sample is uncontaminated by stars that are
not members of the cluster. Techniques for determining cluster membership
therefore play a key role in the investigation of clusters. We present results
on three clusters in the Kepler field of view based on a newly established
technique that uses asteroseismology to identify fore- or background stars in
the field, which demonstrates advantages over classical methods such as
kinematic and photometry measurements. Four previously identified seismic
non-members in NGC6819 are confirmed in this study, and three additional
non-members are found -- two in NGC6819 and one in NGC6791. We further
highlight which stars are, or might be, affected by blending, which needs to be
taken into account when analysing these Kepler data.Comment: 12 pages, 9 figures, 5 tables, accepted by Ap
Gravitational clustering of relic neutrinos and implications for their detection
We study the gravitational clustering of big bang relic neutrinos onto
existing cold dark matter (CDM) and baryonic structures within the flat
CDM model, using both numerical simulations and a semi-analytical
linear technique, with the aim of understanding the neutrinos' clustering
properties for direct detection purposes. In a comparative analysis, we find
that the linear technique systematically underestimates the amount of
clustering for a wide range of CDM halo and neutrino masses. This invalidates
earlier claims of the technique's applicability. We then compute the exact
phase space distribution of relic neutrinos in our neighbourhood at Earth, and
estimate the large scale neutrino density contrasts within the local
Greisen--Zatsepin--Kuzmin zone. With these findings, we discuss the
implications of gravitational neutrino clustering for scattering-based
detection methods, ranging from flux detection via Cavendish-type torsion
balances, to target detection using accelerator beams and cosmic rays. For
emission spectroscopy via resonant annihilation of extremely energetic cosmic
neutrinos on the relic neutrino background, we give new estimates for the
expected enhancement in the event rates in the direction of the Virgo cluster.Comment: 38 pages, 8 embedded figures, iopart.cls; v2: references added, minor
changes in text, to appear in JCA
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