Methylation Status of Imprinted Genes and Repetitive Elements in Sperm DNA from Infertile Males

Stochastic, environmentally and/or genetically induced disturbances in the genome-wide epigenetic reprogramming processes during male germ-cell development may contribute to male infertility. To test this hypothesis, we have studied the methylation levels of 2 paternally (H19 and GTL2) and 5 maternally methylated (LIT1, MEST, NESPAS, PEG3, and SNRPN) imprinted genes, as well as of ALU and LINE1 repetitive elements in 141 sperm samples, which were used for assisted reproductive technologies (ART), including 106 couples with strictly male-factor or combined male and female infertility and 28 couples with strictly female-factor infertility. Aberrant methylation imprints showed a significant association with abnormal semen parameters, but did not seem to influence ART outcome. Repeat methylation also differed significantly between sperm samples from infertile and presumably fertile males. However, in contrast to imprinted genes, ALU methylation had a significant impact on pregnancy and live-birth rate in couples with male-factor or combined infertility. ALU methylation was significantly high-er in sperm samples leading to pregnancy and live-birth than in those that did not. Sperm samples leading to abortions showed significantly lower ALU methylation levels than those leading to the birth of a baby. Copyright (C) 2011 S. Karger AG, Base

Fluid Models of Many-server Queues with Abandonment

We study many-server queues with abandonment in which customers have general service and patience time distributions. The dynamics of the system are modeled using measure- valued processes, to keep track of the residual service and patience times of each customer. Deterministic fluid models are established to provide first-order approximation for this model. The fluid model solution, which is proved to uniquely exists, serves as the fluid limit of the many-server queue, as the number of servers becomes large. Based on the fluid model solution, first-order approximations for various performance quantities are proposed

Pseudo-Riemannian geodesic foliations by circles

We investigate under which assumptions an orientable pseudo-Riemannian geodesic foliations by circles is generated by an $S^1$-action. We construct examples showing that, contrary to the Riemannian case, it is not always true. However, we prove that such an action always exists when the foliation does not contain lightlike leaves, i.e. a pseudo-Riemannian Wadsley's Theorem. As an application, we show that every Lorentzian surface all of whose spacelike/timelike geodesics are closed, is finitely covered by $S^1\times \R$. It follows that every Lorentzian surface contains a non-closed geodesic.Comment: 14 page

Fluid limits for networks with bandwidth sharing and general document size distributions

We consider a stochastic model of Internet congestion control, introduced by Massouli\'{e} and Roberts [Telecommunication Systems 15 (2000) 185--201], that represents the randomly varying number of flows in a network where bandwidth is shared among document transfers. In contrast to an earlier work by Kelly and Williams [Ann. Appl. Probab. 14 (2004) 1055--1083], the present paper allows interarrival times and document sizes to be generally distributed, rather than exponentially distributed. Furthermore, we allow a fairly general class of bandwidth sharing policies that includes the weighted $\alpha$-fair policies of Mo and Walrand [IEEE/ACM Transactions on Networking 8 (2000) 556--567], as well as certain other utility based scheduling policies. To describe the evolution of the system, measure valued processes are used to keep track of the residual document sizes of all flows through the network. We propose a fluid model (or formal functional law of large numbers approximation) associated with the stochastic flow level model. Under mild conditions, we show that the appropriately rescaled measure valued processes corresponding to a sequence of such models (with fixed network structure) are tight, and that any weak limit point of the sequence is almost surely a fluid model solution. For the special case of weighted $\alpha$-fair policies, we also characterize the invariant states of the fluid model.Comment: Published in at http://dx.doi.org/10.1214/08-AAP541 the Annals of Applied Probability (http://www.imstat.org/aap/) by the Institute of Mathematical Statistics (http://www.imstat.org

Epidermal growth factor receptor pathway substrate 8 (Eps8) expression in maturing testis.

AIM: Although epidermal growth factor receptors are expressed in the testes, whether they signal through epidermal growth factor receptor pathway substrate 8 (Eps8) is unknown. Here we evaluated the expression pattern of Eps8 in the maturing testis. METHODS: The expression of Eps8 was analysed by Northern blotting, immunocytochemistry and Western blotting in primary Sertoli cell cultures and in testicular tissue of rodents. RESULTS: Eps8 is specifically expressed in gonocytes, Leydig and Sertoli cells of the neonatal rats and in Leydig and Sertoli cells of the adult rats and mice. Although gonocytes express Eps8, no signal was found in prepubertal or mature spermatogonia and the expression level of Eps8 in Sertoli cells increases with age. No regulation of Eps8 expression in primary immature rat Sertoli cells by Follicle stimulating hormone (FSH) was detected by Western blotting. CONCLUSION: Eps8 seems to be involved in the growth factor-controlled regulation of cell proliferation and differentiation in the seminiferous epithelium. Eps8 is a possible marker for gonocytes and in Sertoli cells it could be involved in crosstalk with other growth factor pathways

A microRNA cluster in the Fragile-X region expressed during spermatogenesis targets FMR1.

Testis-expressed X-linked genes typically evolve rapidly. Here, we report on a testis-expressed X-linked microRNA (miRNA) cluster that despite rapid alterations in sequence has retained its position in the Fragile-X region of the X chromosome in placental mammals. Surprisingly, the miRNAs encoded by this cluster (Fx-mir) have a predilection for targeting the immediately adjacent gene, Fmr1, an unexpected finding given that miRNAs usually act in trans, not in cis Robust repression of Fmr1 is conferred by combinations of Fx-mir miRNAs induced in Sertoli cells (SCs) during postnatal development when they terminate proliferation. Physiological significance is suggested by the finding that FMRP, the protein product of Fmr1, is downregulated when Fx-mir miRNAs are induced, and that FMRP loss causes SC hyperproliferation and spermatogenic defects. Fx-mir miRNAs not only regulate the expression of FMRP, but also regulate the expression of eIF4E and CYFIP1, which together with FMRP form a translational regulatory complex. Our results support a model in which Fx-mir family members act cooperatively to regulate the translation of batteries of mRNAs in a developmentally regulated manner in SCs

Hydrodynamic simulations of the KT Eridani nova super-remnant

A nova super-remnant (NSR) is an immense structure associated with a nova that forms when frequent and recurrent nova eruptions sweep up surrounding interstellar material (ISM) into a high density and distant shell. The prototypical NSR, measuring over 100 pc across, was discovered in 2014 around the annually erupting nova M31N 2008-12a. Hydrodynamical simulations demonstrated that the creation of a dynamic NSR by repeated eruptions transporting large quantities of ISM is not only feasible but that these structures should exist around all novae, whether the white dwarf (WD) is increasing or decreasing in mass. But it is only the recurrent nova (RNe) with the highest WD masses and accretion rates that should host observable NSRs. KT Eridani is, potentially, the eleventh RNe recorded in the Galaxy and is also surrounded by a recently unveiled H{\alpha} shell tens of parsecs across, consistent with a NSR. Through modelling the nova ejecta from KT Eri, we demonstrate that such an observable NSR could form in approximately 50,000 years, which fits with the proper motion history of the nova. We compute the expected H{\alpha} emission from the KT Eri NSR and predict that the structure might be accessible to wide-field X-ray facilities.Comment: 9 pages, 7 figures; Accepted for publication in Monthly Notices of the Royal Astronomical Societ

Convergence of vector bundles with metrics of Sasaki-type

If a sequence of Riemannian manifolds, $X_i$, converges in the pointed Gromov-Hausdorff sense to a limit space, $X_\infty$, and if $E_i$ are vector bundles over $X_i$ endowed with metrics of Sasaki-type with a uniform upper bound on rank, then a subsequence of the $E_i$ converges in the pointed Gromov-Hausdorff sense to a metric space, $E_\infty$. The projection maps $\pi_i$ converge to a limit submetry $\pi_\infty$ and the fibers converge to its fibers; the latter may no longer be vector spaces but are homeomorphic to $\R^k/G$, where $G$ is a closed subgroup of $O(k)$ ---called the {\em wane group}--- that depends on the basepoint and that is defined using the holonomy groups on the vector bundles. The norms $\mu_i=\|\cdot\|_i$ converges to a map $\mu_{\infty}$ compatible with the re-scaling in $\R^k/G$ and the $\R$-action on $E_i$ converges to an $\R-$action on $E_{\infty}$ compatible with the limiting norm. In the special case when the sequence of vector bundles has a uniform lower bound on holonomy radius (as in a sequence of collapsing flat tori to a circle), the limit fibers are vector spaces. Under the opposite extreme, e.g. when a single compact $n$-dimensional manifold is re-scaled to a point, the limit fiber is $\R^n/H$ where $H$ is the closure of the holonomy group of the compact manifold considered. An appropriate notion of parallelism is given to the limiting spaces by considering curves whose length is unchanged under the projection. The class of such curves is invariant under the $\R$-action and each such curve preserves norms. The existence of parallel translation along rectifiable curves with arbitrary initial conditions is also exhibited. Uniqueness is not true in general, but a necessary condition is given in terms of the aforementioned wane groups $G$.Comment: 44 pages, 1 figure, in V.2 added Theorem E and Section 4 on parallelism in the limit space

Targeted expression of human FSH receptor Asp567Gly mutant mRNA in testis of transgenic mice: role of the human FSH receptor promoter.

AIM: To specifically express the Asp567Gly human follicle-stimulating hormone receptor (FSHR) under the control of its promoter to evaluate the phenotypic consequences in the presence of normal pituitary function. METHODS: We produced transgenic mice overexpressing the Asp567Gly human FSHR under the control of a 1.5kb 5'-flanking region fragment of its promoter. RESULTS: Mice were phenotypically normal and fertile. In males, mRNA could be detected in the testis and the brain, indicating that the 1.5kb promoter fragment drives expression not only in the gonads. The testis weight/body weight ratio and the testosterone levels in transgenic and non-transgenic littermates were similar. By in situ hybridisation we found that the transgenic FSHR was highly expressed in Sertoli cells, spermatocytes and round spermatids. However, a radioligand receptor assay failed to show a significant difference in total FSHR binding sites in testis homogenates of transgenic and wild type animals, suggesting that the transgenic FSHR is probably not translated into functional receptor protein. CONCLUSION: A 1.5kb 5'-region of the human FSHR drives mRNA expression of the transgene in the testis but leads to ectopic expression in germ cells and in the brain. No phenotypic consequences could be documented due to the lack of protein expression

Exotic Spaces in Quantum Gravity I: Euclidean Quantum Gravity in Seven Dimensions

It is well known that in four or more dimensions, there exist exotic manifolds; manifolds that are homeomorphic but not diffeomorphic to each other. More precisely, exotic manifolds are the same topological manifold but have inequivalent differentiable structures. This situation is in contrast to the uniqueness of the differentiable structure on topological manifolds in one, two and three dimensions. As exotic manifolds are not diffeomorphic, one can argue that quantum amplitudes for gravity formulated as functional integrals should include a sum over not only physically distinct geometries and topologies but also inequivalent differentiable structures. But can the inclusion of exotic manifolds in such sums make a significant contribution to these quantum amplitudes? This paper will demonstrate that it will. Simply connected exotic Einstein manifolds with positive curvature exist in seven dimensions. Their metrics are found numerically; they are shown to have volumes of the same order of magnitude. Their contribution to the semiclassical evaluation of the partition function for Euclidean quantum gravity in seven dimensions is evaluated and found to be nontrivial. Consequently, inequivalent differentiable structures should be included in the formulation of sums over histories for quantum gravity.Comment: AmsTex, 23 pages 5 eps figures; replaced figures with ones which are hopefully viewable in pdf forma