On asymptotics of the beta-coalescents

We show that the total number of collisions in the exchangeable coalescent process driven by the beta $(1,b)$ measure converges in distribution to a 1-stable law, as the initial number of particles goes to infinity. The stable limit law is also shown for the total branch length of the coalescent tree. These results were known previously for the instance $b=1$, which corresponds to the Bolthausen--Sznitman coalescent. The approach we take is based on estimating the quality of a renewal approximation to the coalescent in terms of a suitable Wasserstein distance. Application of the method to beta $(a,b)$-coalescents with $0<a<1$ leads to a simplified derivation of the known $(2-a)$-stable limit. We furthermore derive asymptotic expansions for the moments of the number of collisions and of the total branch length for the beta $(1,b)$-coalescent by exploiting the method of sequential approximations.Comment: 25 pages, submitted for publicatio

A modified lookdown construction for the Xi-Fleming-Viot process with mutation and populations with recurrent bottlenecks

Let $\Lambda$ be a finite measure on the unit interval. A $\Lambda$-Fleming-Viot process is a probability measure valued Markov process which is dual to a coalescent with multiple collisions ($\Lambda$-coalescent) in analogy to the duality known for the classical Fleming Viot process and Kingman's coalescent, where $\Lambda$ is the Dirac measure in 0. We explicitly construct a dual process of the coalescent with simultaneous multiple collisions ($\Xi$-coalescent) with mutation, the $\Xi$-Fleming-Viot process with mutation, and provide a representation based on the empirical measure of an exchangeable particle system along the lines of Donnelly and Kurtz (1999). We establish pathwise convergence of the approximating systems to the limiting $\Xi$-Fleming-Viot process with mutation. An alternative construction of the semigroup based on the Hille-Yosida theorem is provided and various types of duality of the processes are discussed. In the last part of the paper a population is considered which undergoes recurrent bottlenecks. In this scenario, non-trivial $\Xi$-Fleming-Viot processes naturally arise as limiting models.Comment: 35 pages, 2 figure

Discovery of a small molecule ligand of FRS2 that inhibits invasion and tumor growth

Purpose: Aberrant activation of the fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases drives oncogenic signaling through its proximal adaptor protein FRS2. Precise disruption of this disease-causing signal transmission in metastatic cancers could stall tumor growth and progression. The purpose of this study was to identify a small molecule ligand of FRS2 to interrupt oncogenic signal transmission from activated FGFRs. Methods: We used pharmacophore-based computational screening to identify potential small molecule ligands of the PTB domain of FRS2, which couples FRS2 to FGFRs. We confirmed PTB domain binding of molecules identified with biophysical binding assays and validated compound activity in cell-based functional assays in vitro and in an ovarian cancer model in vivo. We used thermal proteome profiling to identify potential off-targets of the lead compound. Results: We describe a small molecule ligand of the PTB domain of FRS2 that prevents FRS2 activation and interrupts FGFR signaling. This PTB-domain ligand displays on-target activity in cells and stalls FGFR-dependent matrix invasion in various cancer models. The small molecule ligand is detectable in the serum of mice at the effective concentration for prolonged time and reduces growth of the ovarian cancer model in vivo. Using thermal proteome profiling, we furthermore identified potential off-targets of the lead compound that will guide further compound refinement and drug development. Conclusions: Our results illustrate a phenotype-guided drug discovery strategy that identified a novel mechanism to repress FGFR-driven invasiveness and growth in human cancers. The here identified bioactive leads targeting FGF signaling and cell dissemination provide a novel structural basis for further development as a tumor agnostic strategy to repress FGFR- and FRS2-driven tumors. Keywords: Bioactive small molecule compound; Cell invasion; FGFR; FRS2; Protein–protein interaction interference; Thermal proteome profilin

Repair at Single Targeted DNA Double-Strand Breaks in Pluripotent and Differentiated Human Cells

Differences in ex vivo cell culture conditions can drastically affect stem cell physiology. We sought to establish an assay for measuring the effects of chemical, environmental, and genetic manipulations on the precision of repair at a single DNA double-strand break (DSB) in pluripotent and somatic human cells. DSBs in mammalian cells are primarily repaired by either homologous recombination (HR) or nonhomologous end-joining (NHEJ). For the most part, previous studies of DSB repair in human cells have utilized nonspecific clastogens like ionizing radiation, which are highly nonphysiologic, or assayed repair at randomly integrated reporters. Measuring repair after random integration is potentially confounded by locus-specific effects on the efficiency and precision of repair. We show that the frequency of HR at a single DSB differs up to 20-fold between otherwise isogenic human embryonic stem cells (hESCs) based on the site of the DSB within the genome. To overcome locus-specific effects on DSB repair, we used zinc finger nucleases to efficiently target a DSB repair reporter to a safe-harbor locus in hESCs and a panel of somatic human cell lines. We demonstrate that repair at a targeted DSB is highly precise in hESCs, compared to either the somatic human cells or murine embryonic stem cells. Differentiation of hESCs harboring the targeted reporter into astrocytes reduces both the efficiency and precision of repair. Thus, the phenotype of repair at a single DSB can differ based on either the site of damage within the genome or the stage of cellular differentiation. Our approach to single DSB analysis has broad utility for defining the effects of genetic and environmental modifications on repair precision in pluripotent cells and their differentiated progeny

Conditions for exchangeable coalescents to come down from infinity

Non UBCUnreviewedAuthor affiliation: University of TuebingenFacult

PRIMARY PHOTOPHYSICAL PROCESSES IN TRIPLET DURALDEHYDE

$^{1}$E. Migirdicyan, Chem. Phys. Letters 12, 473 (1972). $^{2}$E. Migirdicyan, J. Chem. Phys. 55, 1861 (1971).""Author Institution: Department of Chemistry, University of FloridaThe phosphorescence spectra and lifetimes of 2,4,5-trimethyl-benzaldehyde (duraldehyde) have been measured as a function of temperature ($10-l60^{\circ} K$) in a variety of solvent systems, including crystalline durene. Our spectral results corroborate Mig