Differential role of RB in response to UV and IR damage

The retinoblastoma tumor suppressor (RB) is functionally inactivated in the majority of cancers and is a critical mediator of DNA damage checkpoints. Despite the critical importance of RB function in tumor suppression, the coordinate impact of RB loss on the response to environmental and therapeutic sources of damage has remained largely unexplored. Here, we utilized a conditional knockout system to ablate RB in adult fibroblasts. This model system enabled us to investigate the temporal role of RB loss on cell cycle checkpoints and DNA damage repair following ultraviolet (UV) and ionizing radiation (IR) damage. We demonstrate that RB loss compromises rapid cell cycle arrest following UV and IR exposure in adult primary cells. Detailed kinetic analysis of the checkpoint response revealed that disruption of the checkpoint is concomitant with RB target gene deregulation, and is not simply a manifestation of chronic RB loss. RB loss had a differential effect upon repair of the major DNA lesions induced by IR and UV. Whereas RB did not affect resolution of DNA double-strand breaks, RB-deficient cells exhibited accelerated repair of pyrimidine pyrimidone photoproducts (6-4 PP). In parallel, this repair was coupled with enhanced expression of specific factors and the behavior of proliferating cell nuclear antigen (PCNA) recruitment to replication and repair foci. Thus, RB loss and target gene deregulation hastens the repair of specific lesions distinct from its ubiquitous role in checkpoint abrogation

A direct D-bar reconstruction algorithm for recovering a complex conductivity in 2-D

A direct reconstruction algorithm for complex conductivities in $W^{2,\infty}(\Omega)$, where $\Omega$ is a bounded, simply connected Lipschitz domain in $\mathbb{R}^2$, is presented. The framework is based on the uniqueness proof by Francini [Inverse Problems 20 2000], but equations relating the Dirichlet-to-Neumann to the scattering transform and the exponentially growing solutions are not present in that work, and are derived here. The algorithm constitutes the first D-bar method for the reconstruction of conductivities and permittivities in two dimensions. Reconstructions of numerically simulated chest phantoms with discontinuities at the organ boundaries are included.Comment: This is an author-created, un-copyedited version of an article accepted for publication in [insert name of journal]. IOP Publishing Ltd is not responsible for any errors or omissions in this version of the manuscript or any version derived from it. The Version of Record is available online at 10.1088/0266-5611/28/9/09500

Single-cell profiling for advancing birth defects research and prevention

Cellular analysis of developmental processes and toxicities has traditionally entailed bulk methods (e.g., transcriptomics) that lack single cell resolution or tissue localization methods (e.g., immunostaining) that allow only a few genes to be monitored in each experiment. Recent technological advances have enabled interrogation of genomic function at the single-cell level, providing new opportunities to unravel developmental pathways and processes with unprecedented resolution. Here, we review emerging technologies of single-cell RNA-sequencing (scRNA-seq) to globally characterize the gene expression sets of different cell types and how different cell types emerge from earlier cell states in development. Cell atlases of experimental embryology and human embryogenesis at single-cell resolution will provide an encyclopedia of genes that define key stages from gastrulation to organogenesis. This technology, combined with computational models to discover key organizational principles, was recognized by Science magazine as the “Breakthrough of the year” for 2018 due to transformative potential on the way we study how human cells mature over a lifetime, how tissues regenerate, and how cells change in diseases (e.g., patient-derived organoids to screen disease-specific targets and design precision therapy). Profiling transcriptomes at the single-cell level can fulfill the need for greater detail in the molecular progression of all cell lineages, from pluripotency to adulthood and how cell–cell signaling pathways control progression at every step. Translational opportunities emerge for elucidating pathogenesis of genetic birth defects with cellular precision and improvements for predictive toxicology of chemical teratogenesis

Extended modular operad

This paper is a sequel to [LoMa] where moduli spaces of painted stable curves were introduced and studied. We define the extended modular operad of genus zero, algebras over this operad, and study the formal differential geometric structures related to these algebras: pencils of flat connections and Frobenius manifolds without metric. We focus here on the combinatorial aspects of the picture. Algebraic geometric aspects are treated in [Ma2].Comment: 38 pp., amstex file, no figures. This version contains additional references and minor change

A two-fluid model describing the finite-collisionality, stationary Alfvén wave in anisotropic plasma

The stationary inertial Alfvén (StIA) wave (Knudsen, 1996) was predicted for cold, collisionless plasma. The model was generalized (Finnegan et al., 2008) to include nonzero values of electron and ion collisional resistivity and thermal pressure. Here, the two-fluid model is further generalized to include anisotropic thermal pressure. A bounded range of values of parallel electron drift velocity is found that excludes periodic stationary Alfvén wave solutions. This exclusion region depends on the value of the local Alfvén speed VA, plasma beta perpendicular to the magnetic field β⊥ and electron temperature anisotropy

Studies of an artificially generated electrode effect at ground level

International audienceThe outdoor experiments, using a metallic grid above the ground surface, have yielded well-defined vertical profiles of the space-charge density. The profiles showed strong evidence for the existence of an electrode effect, which could be named the artificial electrode effect and can serve as a very useful and well-controlled model for the study of atmospheric electric processes in the atmospheric surface layer. The build-up or break-down of an electrode-effect layer occurred in a time of the order of 10 s under the experimental conditions realized. The artificially generated electrode effect is dependent on the electrical field strength supplied, wind speed, turbulent mixing and ion mobilities. Wind speed and ion mobility seem to be the dominant factors, defining space-charge density profiles. A theoretical model for the artificial electrode effect has been developed, taking into account turbulent mixing of charged particles in the air flow with the logarithmic profile of the wind velocity. The numerical analysis of the boundary value problem for the two-dimensional equations for the light ion concentrations has been performed. The model presented shows a qualitative agreement of calculated space-charge profiles with measured ones, and explains the dependence of the artificial electrode effect on the dominant control parameters. The limiting conditions for the developed theory are discussed

Influence of mountain waves and NAT nucleation mechanisms on Polar Stratospheric Cloud formation at local and synoptic scales during the 1999?2000 Arctic winter

International audienceA scheme for introducing mountain wave-induced temperature pertubations in a microphysical PSC model has been developed. A data set of temperature fluctuations attributable to mountain waves as computed by the Mountain Wave Forecast Model (MWFM-2) has been used for the study. The PSC model has variable microphysics, enabling different nucleation mechanisms for nitric acid trihydrate, NAT, to be employed. In particular, the difference between the formation of NAT and ice particles in a scenario where NAT formation is not dependent on preexisting ice particles, allowing NAT to form at temperatures above the ice frost point, Tice, and a scenario, where NAT nucleation is dependent on preexisting ice particles, is examined. The performance of the microphysical model in the different microphysical scenarios and a number of temperature scenarios with and without the influence of mountain waves is tested through comparisons with lidar measurements of PSCs made from the NASA DC-8 on 23 and 25 January during the SOLVE/THESEO 2000 campaign in the 1999?2000 winter and the effect of mountain waves on local PSC production is evaluated in the different microphysical scenarios. Mountain wave-induced temperature fluctuations are introduced in vortex-covering model runs, extending the full 1999?2000 winter season, and the effect of mountain waves on large-scale PSC production is estimated in the different microphysical scenarios