Inference of single-cell phylogenies from lineage tracing data using Cassiopeia.

The pairing of CRISPR/Cas9-based gene editing with massively parallel single-cell readouts now enables large-scale lineage tracing. However, the rapid growth in complexity of data from these assays has outpaced our ability to accurately infer phylogenetic relationships. First, we introduce Cassiopeia-a suite of scalable maximum parsimony approaches for tree reconstruction. Second, we provide a simulation framework for evaluating algorithms and exploring lineage tracer design principles. Finally, we generate the most complex experimental lineage tracing dataset to date, 34,557 human cells continuously traced over 15 generations, and use it for benchmarking phylogenetic inference approaches. We show that Cassiopeia outperforms traditional methods by several metrics and under a wide variety of parameter regimes, and provide insight into the principles for the design of improved Cas9-enabled recorders. Together, these should broadly enable large-scale mammalian lineage tracing efforts. Cassiopeia and its benchmarking resources are publicly available at www.github.com/YosefLab/Cassiopeia

The Population of Damped Lyman-alpha and Lyman Limit Systems in the Cold Dark Matter Model

Lyman limit and damped Lyman-alpha absorption systems probe the distribution of collapsed, cold gas at high redshift. Numerical simulations that incorporate gravity and gas dynamics can predict the abundance of such absorbers in cosmological models. We develop a semi-analytical method to correct the numerical predictions for the contribution of unresolved low mass halos, and we apply this method to the Katz et al. (1996) simulation of the standard cold dark matter model ($\Omega=1$, $h=0.5$, $\Omega_b=0.05$, $\sigma_8=0.7$). Using this simulation and higher resolution simulations of individual low mass systems, we determine the relation between a halo's circular velocity $v_c$ and its cross section for producing Lyman limit or damped absorption. We combine this relation with the Press-Schechter formula for the abundance of halos to compute the number of absorbers per unit redshift. The resolution correction increases the predicted abundances by about a factor of two at z=2, 3, and 4, bringing the predicted number of damped absorbers into quite good agreement with observations. Roughly half of the systems reside in halos with circular velocities v_c>100\kms and half in halos with 35\kms. Halos with v_c>150\kms typically harbor two or more systems capable of producing damped absorption. Even with the resolution correction, the predicted abundance of Lyman limit systems is a factor of three below observational estimates, signifying either a failure of standard CDM or a failure of these simulations to resolve the systems responsible for most Lyman limit absorption. By comparing simulations with and without star formation, we find that depletion of the gas supply by star formation affects absorption line statistics at $z>=2$ only for column densities exceeding $N_{HI}=10^{22} cm^{-2}$.Comment: AASlatex, 17 pages w/ 3 embedded ps figures. Submitted to Ap

Simulations of Damped Lyman-Alpha and Lyman Limit Absorbers in Different Cosmologies: Implications for Structure Formation at High Redshift

We use hydrodynamic cosmological simulations to study damped Lyman-alpha (DLA) and Lyman limit (LL) absorption at redshifts z=2-4 in five variants of the cold dark matter scenario. Our standard simulations resolve the formation of dense concentrations of neutral gas in halos with circular velocity v_c roughly 140 km/s for Omega_m=1 and 90 km/s for Omega_m=0.4, at z=2; an additional LCDM simulation resolves halos down to v_c approximately 50 km/s at z=3. We find a clear relation between HI column density and projected distance to the center of the nearest galaxy, with DLA absorption usually confined to galactocentric radii less than 10-15 kpc and LL absorption arising out to projected separations of 30 kpc or more. Detailed examination provides evidence of non-equilibrium effects on absorption cross-section. If we consider only absorption in the halos resolved by our standard simulations, then all five models fall short of reproducing the observed abundance of DLA and LL systems at these redshifts. If we extrapolate to lower halo masses, we find all four models are consistent with the observed abundance of DLA systems if the the extrapolated behavior extends to circular velocities roughly 50-80 km/s, and they may produce too much absorption if the relation continues to 40 km/s. Our results suggest that LL absorption is closely akin to DLA absorption, arising in less massive halos or at larger galactocentric radii but not caused by processes acting on a radically different mass scale.Comment: 33 pages with 10 embedded EPS figures. Substantially revised and updated from original version. Includes new high-resolution simulations. Accepted for publication in the Ap

Molecular recording of mammalian embryogenesis.

Ontogeny describes the emergence of complex multicellular organisms from single totipotent cells. This field is particularly challenging in mammals, owing to the indeterminate relationship between self-renewal and differentiation, variation in progenitor field sizes, and internal gestation in these animals. Here we present a flexible, high-information, multi-channel molecular recorder with a single-cell readout and apply it as an evolving lineage tracer to assemble mouse cell-fate maps from fertilization through gastrulation. By combining lineage information with single-cell RNA sequencing profiles, we recapitulate canonical developmental relationships between different tissue types and reveal the nearly complete transcriptional convergence of endodermal cells of extra-embryonic and embryonic origins. Finally, we apply our cell-fate maps to estimate the number of embryonic progenitor cells and their degree of asymmetric partitioning during specification. Our approach enables massively parallel, high-resolution recording of lineage and other information in mammalian systems, which will facilitate the construction of a quantitative framework for understanding developmental processes

Testing Cosmological Models Against the Abundance of Damped Lyman-Alpha Absorbers

We calculate the number of damped Lyman-alpha absorbers expected in various popular cosmological models as a function of redshift and compare our predictions with observed abundances. The Press-Schechter formalism is used to obtain the distribution of halos with circular velocity in different cosmologies, and we calibrate the relation between circular velocity and absorption cross-section using detailed gas dynamical simulations of a ``standard'' cold dark matter (CDM) model. Because of this calibration, our approach makes more realistic assumptions about the absorption properties of collapsed objects than previous, analytic calculations of the damped Lyman-alpha abundance. CDM models with Omega_0=1, H_0=50, baryon density Omega_b=0.05, and scale-invariant primeval fluctuations reproduce the observed incidence and redshift evolution of damped Lyman-alpha absorption to within observational uncertainty, for both COBE normalization (sigma_8=1.2) and a lower normalization (sigma_8=0.7) that better matches the observed cluster abundance at z=0. A tilted (n=0.8, sigma_8=0.7) CDM model tends to underproduce absorption, especially at z=4. With COBE normalization, a CDM model with Omega_0=0.4, Omega_{Lambda}=0.6 gives an acceptable fit to the observed absorption; an open CDM model is marginally acceptable if Omega_0 is at least 0.4 and strongly inconsistent with the z=4 data if Omega_0=0.3. Mixed dark matter models tend not to produce sufficient absorption, being roughly comparable to tilted CDM models if Omega_{nu} = 0.2 and failing drastically if Omega_{nu} = 0.3.Comment: AASlatex, 13 pages w/ 2 embedded ps figures. To be published in ApJ, Sept. 1, 199

Z2_2 topology and superconductivity from symmetry lowering of a 3D Dirac Metal Au2_2Pb

3D Dirac semi-metals (DSMs) are materials that have massless Dirac electrons and exhibit exotic physical properties It has been suggested that structurally distorting a DSM can create a Topological Insulator (TI), but this has not yet been experimentally verified. Furthermore, quasiparticle excitations known as Majorana Fermions have been theoretically proposed to exist in materials that exhibit superconductivity and topological surface states. Here we show that the cubic Laves phase Au$_2$Pb has a bulk Dirac cone above 100 K that gaps out upon cooling at a structural phase transition to create a topologically non trivial phase that superconducts below 1.2 K. The nontrivial Z$_2$ = -1 invariant in the low temperature phase indicates that Au$_2$Pb in its superconducting state must have topological surface states. These characteristics make Au$_2$Pb a unique platform for studying the transition between bulk Dirac electrons and topological surface states as well as studying the interaction of superconductivity with topological surface states

Plasma Wakefield Acceleration for Ultrahigh Energy Cosmic Rays

A cosmic acceleration mechanism is introduced which is based on the wakefields excited by the Alfven shocks in a relativistically flowing plasma, where the energy gain per distance of a test particle is Lorentz invariant. We show that there exists a threshold condition for transparency below which the accelerating particle is collision-free and suffers little energy loss in the plasma medium. The stochastic encounters of the random accelerating-decelerating phases results in a power-law energy spectrum: f(e) 1/e^2. The environment suitable for such plasma wakefield acceleration can be cosmically abundant. As an example, we discuss the possible production of super-GZK ultra high energy cosmic rays (UHECR) through this mechanism in the atmosphere of gamma ray bursts. We show that the acceleration gradient can be as high as G ~ 10^16 eV/cm. The estimated event rate in our model agrees with that from UHECR observations.Comment: 11 pages, 1 figure, submitted to Phys. Rev. Let

Brief of Corporate Law Professors as Amici Curie in Support of Respondents

The Supreme Court has looked to the rights of corporate shareholders in determining the rights of union members and non-members to control political spending, and vice versa. The Court sometimes assumes that if shareholders disapprove of corporate political expression, they can easily sell their shares or exercise control over corporate spending. This assumption is mistaken. Because of how capital is saved and invested, most individual shareholders cannot obtain full information about corporate political activities, even after the fact, nor can they prevent their savings from being used to speak in ways with which they disagree. Individual shareholders have no “opt out” rights or practical ability to avoid subsidizing corporate political expression with which they disagree. Nor do individuals have the practical option to refrain from putting their savings into equity investments, as doing so would impose damaging economic penalties and ignore conventional financial guidance for individual investors

Gemini Planet Imager Observational Calibrations VI: Photometric and Spectroscopic Calibration for the Integral Field Spectrograph

The Gemini Planet Imager (GPI) is a new facility instrument for the Gemini Observatory designed to provide direct detection and characterization of planets and debris disks around stars in the solar neighborhood. In addition to its extreme adaptive optics and corona graphic systems which give access to high angular resolution and high-contrast imaging capabilities, GPI contains an integral field spectrograph providing low resolution spectroscopy across five bands between 0.95 and 2.5 $\mu$m. This paper describes the sequence of processing steps required for the spectro-photometric calibration of GPI science data, and the necessary calibration files. Based on calibration observations of the white dwarf HD 8049B we estimate that the systematic error in spectra extracted from GPI observations is less than 5%. The flux ratio of the occulted star and fiducial satellite spots within coronagraphic GPI observations, required to estimate the magnitude difference between a target and any resolved companions, was measured in the $H$-band to be $\Delta m = 9.23\pm0.06$ in laboratory measurements and $\Delta m = 9.39\pm 0.11$ using on-sky observations. Laboratory measurements for the $Y$, $J$, $K1$ and $K2$ filters are also presented. The total throughput of GPI, Gemini South and the atmosphere of the Earth was also measured in each photometric passband, with a typical throughput in $H$-band of 18% in the non-coronagraphic mode, with some variation observed over the six-month period for which observations were available. We also report ongoing development and improvement of the data cube extraction algorithm.Comment: 15 pages, 6 figures. Proceedings of the SPIE, 9147-30