Review: Genetic manipulation of the rodent placenta

The principal role of the placenta is the maintenance of pregnancy and promotion of fetal growth and viability. The use of transgenic rodents has greatly enhanced our understanding of placental development and function. However, embryonic lethality is often a confounding variable in determining whether a genetic modification adversely affected placental development. In these cases, it is beneficial to specifically manipulate the placental genome. The purpose of this review is to summarize available methodologies for specific genetic modification of the rodent placenta. By restricting genetic alterations to the trophoblast lineage, it is possible to gain a deeper understanding of placental development that perhaps will lead to gene-targeted therapies to rescue irregular placentation in transgenic animals or in women at high-risk for placenta-associated pregnancy complications

Rat placentation: An experimental model for investigating the hemochorial maternal-fetal interface

The rat possesses hemochorial placentation with deep intrauterine trophoblast cell invasion and trophoblast-directed uterine spiral artery remodeling; features shared with human placentation. Recognition of these similarities spurred the establishment of in vitro and in vivo research methods using the rat as an animal model to address mechanistic questions regarding development of the hemochorial placenta. The purpose of this review is to provide the requisite background to help move the rat to the forefront in placentation research. © 2012 Elsevier Ltd. All rights reserved

Adaptive mechanisms controlling uterine spiral artery remodeling during the establishment of pregnancy

Implantation of the embryo into the uterus triggers the initiation of hemochorial placentation. The hemochorial placenta facilitates the acquisition of maternal resources required for embryo/fetal growth. Uterine spiral arteries form the nutrient supply line for the placenta and fetus. This vascular conduit undergoes gestation stage-specific remodeling directed by maternal natural killer cells and embryo-derived invasive trophoblast lineages. The placentation site, including remodeling of the uterine spiral arteries, is shaped by environmental challenges. In this review, we discuss the cellular participants controlling pregnancy-dependent uterine spiral artery remodeling and mechanisms responsible for their development and function. © 2014 UBC Press

Missing physics in stick-slip dynamics of a model for peeling of an adhesive tape

It is now known that the equations of motion for the contact point during peeling of an adhesive tape mounted on a roll introduced earlier are singular and do not support dynamical jumps across the two stable branches of the peel force function. By including the kinetic energy of the tape in the Lagrangian, we derive equations of motion that support stick-slip jumps as a natural consequence of the inherent dynamics. In the low mass limit, these equations reproduce solutions obtained using a differential-algebraic algorithm introduced for the earlier equations. Our analysis also shows that mass of the ribbon has a strong influence on the nature of the dynamics.Comment: Accepted for publication in Phys. Rev. E (Rapid Communication

Dynamics of stick-slip in peeling of an adhesive tape

We investigate the dynamics of peeling of an adhesive tape subjected to a constant pull speed. We derive the equations of motion for the angular speed of the roller tape, the peel angle and the pull force used in earlier investigations using a Lagrangian. Due to the constraint between the pull force, peel angle and the peel force, it falls into the category of differential-algebraic equations requiring an appropriate algorithm for its numerical solution. Using such a scheme, we show that stick-slip jumps emerge in a purely dynamical manner. Our detailed numerical study shows that these set of equations exhibit rich dynamics hitherto not reported. In particular, our analysis shows that inertia has considerable influence on the nature of the dynamics. Following studies in the Portevin-Le Chatelier effect, we suggest a phenomenological peel force function which includes the influence of the pull speed. This reproduces the decreasing nature of the rupture force with the pull speed observed in experiments. This rich dynamics is made transparent by using a set of approximations valid in different regimes of the parameter space. The approximate solutions capture major features of the exact numerical solutions and also produce reasonably accurate values for the various quantities of interest.Comment: 12 pages, 9 figures. Minor modifications as suggested by refere

Increases in plasma sheet temperature with solar wind driving during substorm growth phases

During the substorm growth phase, magnetic reconnection extracts ~10^15 J from the solar wind through magnetic reconnection at the magnetopause, which is then stored in the magnetotail lobes. Plasma sheet pressure then increases to balance magnetic flux density increases in the lobes. We examine plasma sheet pressure, density and temperature during substorm growth phases using nine years of Cluster data (>316,000 data points). We show that plasma sheet pressure and temperature are higher during growth phases with higher solar wind driving whereas the density is approximately constant. We also show a weak correlation between plasma sheet temperature before onset and the minimum SuperMAG SML auroral index in the subsequent substorm. We discuss how energization of the plasma sheet before onset may result from thermodynamically adiabatic processes; how hotter plasma sheets may result in magnetotail instabilities and how this relates to the onset and size of the subsequent substorm expansion phase

A functional selection of viral genetic elements in cultured cells to identify hepatitis C virus RNA translation inhibitors†

We developed a functional selection system based on randomized genetic elements (GE) to identify potential regulators of hepatitis C virus (HCV) RNA translation, a process initiated by an internal ribosomal entry site (IRES). A retroviral HCV GE library was introduced into HepG2 cells, stably expressing the Herpes simplex virus thymidine kinase (HSV-TK) under the control of the HCV IRES. Cells that expressed transduced GEs inhibiting HSV-TK were selected via their resistance to ganciclovir. Six major GEs were rescued by PCR on the selected cell DNA and identified as HCV elements. We validated our strategy by further studying the activity of one of them, GE4, encoding the 5′ end of the viral NS5A gene. GE4 inhibited HCV IRES-, but not cap-dependent, reporter translation in human hepatic cell lines and inhibited HCV infection at a post-entry step, decreasing by 85% the number of viral RNA copies. This method can be applied to the identification of gene expression regulators

Clinical significance of genetic aberrations in secondary acute myeloid leukemia

The study aimed to identify genetic lesions associated with secondary acute myeloid leukemia (sAML) in comparison with AML arising de novo (dnAML) and assess their impact on patients' overall survival (OS). High-resolution genotyping and loss of heterozygosity mapping was performed on DNA samples from 86 sAML and 117 dnAML patients, using Affymetrix Genome-Wide Human SNP 6.0 arrays. Genes TP53, RUNX1, CBL, IDH1/2, NRAS, NPM1, and FLT3 were analyzed for mutations in all patients. We identified 36 recurrent cytogenetic aberrations (more than five events). Mutations in TP53, 9pUPD, and del7q (targeting CUX1 locus) were significantly associated with sAML, while NPM1 and FLT3 mutations associated with dnAML. Patients with sAML carrying TP53 mutations demonstrated lower 1-year OS rate than those with wild-type TP53 (14.3% +/- 9.4% vs. 35.4% +/- 7.2%; P = 0.002), while complex karyotype, del7q (CUX1) and del7p (IKZF1) showed no significant effect on OS. Multivariate analysis confirmed that mutant TP53 was the only independent adverse prognostic factor for OS in sAML (hazard ratio 2.67; 95% CI: 1.335.37; P = 0.006). Patients with dnAML and complex karyotype carried sAML-associated defects (TP53 defects in 54.5%, deletions targeting FOXP1 and ETV6 loci in 45.4% of the cases). We identified several co-occurring lesions associated with either sAML or dnAML diagnosis. Our data suggest that distinct genetic lesions drive leukemogenesis in sAML. High karyotype complexity of sAML patients does not influence OS. Somatic mutations in TP53 are the only independent adverse prognostic factor in sAML. Patients with dnAML and complex karyotype show genetic features associated with sAML and myeloproliferative neoplasms. Am. J. Hematol., 2012

Three-dimensional microfabrication using two-photon-activated chemistry

Photochemical reactions which can be activated by the simultaneous absorption of two photons provide a means for single-step fabrication of complex 3D microstructures. These types of structures are needed for a wide range of applications, including microfluidics, electrooptics, and micro-electromechanical systems. We have shown that chromophores can be engineered to have both large two-photon absorptivities as well as an efficient means for activating chemical processes, such as radical polymerization, subsequent to the photoexcitation. Chromophores designed following this strategy two-photon-activate the radical polymerization of acrylates at lower incident laser powers than conventional UV initiators. Efficient two-photon photopolymer resins based on these chromophores were used in the fabrication of complex microarchitectures, such as photonic bandgap structures and tapered waveguides. We have devised a strategy which allows this approach to be extended to other chemical systems