The inevitability of unconditionally deleterious substitutions during adaptation

Studies on the genetics of adaptation typically neglect the possibility that a deleterious mutation might fix. Nonetheless, here we show that, in many regimes, the first substitution is most often deleterious, even when fitness is expected to increase in the long term. In particular, we prove that this phenomenon occurs under weak mutation for any house-of-cards model with an equilibrium distribution. We find that the same qualitative results hold under Fisher's geometric model. We also provide a simple intuition for the surprising prevalence of unconditionally deleterious substitutions during early adaptation. Importantly, the phenomenon we describe occurs on fitness landscapes without any local maxima and is therefore distinct from "valley-crossing". Our results imply that the common practice of ignoring deleterious substitutions leads to qualitatively incorrect predictions in many regimes. Our results also have implications for the substitution process at equilibrium and for the response to a sudden decrease in population size.Comment: Corrected typos and minor errors in Supporting Informatio

Studies on mouse Moloney virus induced tumours: I. The detection of p30 as a cytotoxic target on murine Moloney leukaemic spleen cells, and on an in vitro Moloney sarcoma line by antibody mediated cytotoxicity.

Antigenic determinants of p30, the most abundant internal virion protein of C type RNA viruses, were detected on the surface of spleen cells from mice bearing Moloney leukaemia and on an in vitro line of Moloney sarcoma, MSC. On both cell types, these determinants on the p30 molecules served as cytotoxic targets in a xenogenic complement dependent antibody mediated 51Cr release assay. Two antisera were used: a rat anti MLV -M induced lymphoma serum, and an antiserum raised in goats to either disrupted FeLV. The cytotoxic target antigens of these antisera were analysed by inhibition of cytotoxicity with viral and cellular proteins

Late-Time Convection in the Collapse of a 23 Solar Mass Star

The results of a 3-dimensional SNSPH simulation of the core collapse of a 23 solar mass star are presented. This simulation did not launch an explosion until over 600ms after collapse, allowing an ideal opportunity to study the evolution and structure of the convection below the accretion shock to late times. This late-time convection allows us to study several of the recent claims in the literature about the role of convection: is it dominated by an l=1 mode driven by vortical-acoustic (or other) instability, does it produce strong neutron star kicks, and, finally, is it the key to a new explosion mechanism? The convective region buffets the neutron star, imparting a 150-200 km/s kick. Because the l=1 mode does not dominate the convection, the neutron star does not achieve large (>450 km/s) velocities. Finally, the neutron star in this simulation moves, but does not develop strong oscillations, the energy source for a recently proposed supernova engine. We discuss the implications these results have on supernovae, hypernovae (and gamma-ray bursts), and stellar-massed black holes.Comment: 31 pages (including 13 figures), submitted to Ap

Frontostriatal Maturation Predicts Cognitive Control Failure to Appetitive Cues in Adolescents

Adolescent risk-taking is a public health issue that increases the odds of poor lifetime outcomes. One factor thought to influence adolescents' propensity for risk-taking is an enhanced sensitivity to appetitive cues, relative to an immature capacity to exert sufficient cognitive control. We tested this hypothesis by characterizing interactions among ventral striatal, dorsal striatal, and prefrontal cortical regions with varying appetitive load using fMRI scanning. Child, teen, and adult participants performed a go/no-go task with appetitive (happy faces) and neutral cues (calm faces). Impulse control to neutral cues showed linear improvement with age, whereas teens showed a nonlinear reduction in impulse control to appetitive cues. This performance decrement in teens was paralleled by enhanced activity in the ventral striatum. Prefrontal cortical recruitment correlated with overall accuracy and showed a linear response with age for no-go versus go trials. Connectivity analyses identified a ventral frontostriatal circuit including the inferior frontal gyrus and dorsal striatum during no-go versus go trials. Examining recruitment developmentally showed that teens had greater between-subject ventral-dorsal striatal coactivation relative to children and adults for happy no-go versus go trials. These findings implicate exaggerated ventral striatal representation of appetitive cues in adolescents relative to an intermediary cognitive control response. Connectivity and coactivity data suggest these systems communicate at the level of the dorsal striatum differentially across development. Biased responding in this system is one possible mechanism underlying heightened risk-taking during adolescence

Up-Regulated Expression of Extracellular Matrix Remodeling Genes in Phagocytically Challenged Trabecular Meshwork Cells

Cells in the trabecular meshwork (TM), the tissue responsible for draining aqueous humor out of the eye, are known to be highly phagocytic. Phagocytic function in TM cells is thought to play an important role in the normal functioning of the outflow pathway. Dysfunction of phagocytosis could lead to abnormalities of outflow resistance and increased intraocular pressure (IOP). However, the molecular mechanisms triggered by phagocytosis in TM cells are completely unknown.Gene expression profile analysis of human TM cells phagocytically challenged to E. coli or pigment under physiological and oxidative stress environment were performed using Affymetrix U133 plus 2.0 array and analyzed with Genespring GX. Despite the differential biological response elicited by E. coli and pigment particles, a number of genes, including MMP1, MMP3, TNFSF11, DIO2, KYNU, and KCCN2 showed differential expression with both phagocytic ligands in all conditions. Data was confirmed by qPCR in both human and porcine TM cells. Metacore pathway analysis and the usage of recombinant adenovirus encoding the dominant negative mutant of IkB identified NF-κB as a transcription factor mediating the up-regulation of at least MMP1 and MMP3 in TM cells with phagocytosis. In-gel zymography demonstrated increased collagenolytic and caseinolytic activities in the culture media of TM cells challenge to E. coli. In addition, collagenolytic I activity was further confirmed using the self-quenched fluorescent substrate DQ-Collagen I.Here we report for the first time the differential gene expression profile of TM cells phagocytically challenged with either E. coli or pigment. Our data indicate a potential role of phagocytosis in outflow pathway tissue homeostasis through the up-regulation and/or proteolytic activation of extracellular matrix remodeling genes

Energy Density-Flux Correlations in an Unusual Quantum State and in the Vacuum

In this paper we consider the question of the degree to which negative and positive energy are intertwined. We examine in more detail a previously studied quantum state of the massless minimally coupled scalar field, which we call a ``Helfer state''. This is a state in which the energy density can be made arbitrarily negative over an arbitrarily large region of space, but only at one instant in time. In the Helfer state, the negative energy density is accompanied by rapidly time-varying energy fluxes. It is the latter feature which allows the quantum inequalities, bounds which restrict the magnitude and duration of negative energy, to hold for this class of states. An observer who initially passes through the negative energy region will quickly encounter fluxes of positive energy which subsequently enter the region. We examine in detail the correlation between the energy density and flux in the Helfer state in terms of their expectation values. We then study the correlation function between energy density and flux in the Minkowski vacuum state, for a massless minimally coupled scalar field in both two and four dimensions. In this latter analysis we examine correlation functions rather than expectation values. Remarkably, we see qualitatively similar behavior to that in the Helfer state. More specifically, an initial negative energy vacuum fluctuation in some region of space is correlated with a subsequent flux fluctuation of positive energy into the region. We speculate that the mechanism which ensures that the quantum inequalities hold in the Helfer state, as well as in other quantum states associated with negative energy, is, at least in some sense, already ``encoded'' in the fluctuations of the vacuum.Comment: 21 pages, 7 figures; published version with typos corrected and one added referenc

The Orbiter Stability Experiment on STS-40

The Orbiter Stability Experiment (OSE) was developed to evaluate the steadiness of the STS Orbiter as a potential platform for instrumentation that would image the Sun in its extreme ultraviolet and soft X-ray radiations. We were interested in any high frequency motions of the Orbiter's orientation due to normal operations and manned activities. Preliminary results are presented of the observations. Other than the expected slow motion of the Orbiter within the specified angular deadband of 0.1 degrees during the observations, it was found that high frequency (above 1 Hz) angular motions (jitter) were not detectable at the 0.25 arc sec detection limit of the most sensitive detector, for most of the period of observation. No high frequency motions were recorded during intervals that were identified with vernier thruster firings. However, one short interval with detectable spectral power to a frequency of 10 Hz has been found to date. It has not yet been correlated with a particular activity going on at the time. The results of the observations may also be of value in assessing perturbations to the Orbiter's micro-gravity environment produced by normal operations

Gravitational Waves from Mergin Compact Binaries: How Accurately Can One Extract the Binary's Parameters from the Inspiral Waveform?

The most promising source of gravitational waves for the planned detectors LIGO and VIRGO are merging compact binaries, i.e., neutron star/neutron star (NS/NS), neutron star/black hole (NS/BH), and black hole/black-hole (BH/BH) binaries. We investigate how accurately the distance to the source and the masses and spins of the two bodies will be measured from the gravitational wave signals by the three detector LIGO/VIRGO network using ``advanced detectors'' (those present a few years after initial operation). The combination ${\cal M} \equiv (M_1 M_2)^{3/5}(M_1 +M_2)^{-1/5}$ of the masses of the two bodies is measurable with an accuracy $\approx 0.1\%-1\%$. The reduced mass is measurable to $\sim 10\%-15\%$ for NS/NS and NS/BH binaries, and $\sim 50\%$ for BH/BH binaries (assuming $10M_\odot$ BH's). Measurements of the masses and spins are strongly correlated; there is a combination of $\mu$ and the spin angular momenta that is measured to within $\sim 1\%$. We also estimate that distance measurement accuracies will be $\le 15\%$ for $\sim 8\%$ of the detected signals, and $\le 30\%$ for $\sim 60\%$ of the signals, for the LIGO/VIRGO 3-detector network.Comment: 103 pages, 20 figures, submitted to Phys Rev D, uses revtex macros, Caltech preprint GRP-36

Semiclassical Gravity Theory and Quantum Fluctuations

We discuss the limits of validity of the semiclassical theory of gravity in which a classical metric is coupled to the expectation value of the stress tensor. It is argued that this theory is a good approximation only when the fluctuations in the stress tensor are small. We calculate a dimensionless measure of these fluctuations for a scalar field on a flat background in particular cases, including squeezed states and the Casimir vacuum state. It is found that the fluctuations are small for states which are close to a coherent state, which describes classical behavior, but tend to be large otherwise. We find in all cases studied that the energy density fluctuations are large whenever the local energy density is negative. This is taken to mean that the gravitational field of a system with negative energy density, such as the Casimir vacuum, is not described by a fixed classical metric but is undergoing large metric fluctuations. We propose an operational scheme by which one can describe a fluctuating gravitational field in terms of the statistical behavior of test particles. For this purpose we obtain an equation of the form of the Langevin equation used to describe Brownian motion.Comment: In REVTEX. 20pp + 4 figures(not included, available upon request) TUTP-93-

Thermal Particle Creation in Cosmological Spacetimes: A Stochastic Approach

The stochastic method based on the influence functional formalism introduced in an earlier paper to treat particle creation in near-uniformly accelerated detectors and collapsing masses is applied here to treat thermal and near-thermal radiance in certain types of cosmological expansions. It is indicated how the appearance of thermal radiance in different cosmological spacetimes and in the two apparently distinct classes of black hole and cosmological spacetimes can be understood under a unifying conceptual and methodological framework.Comment: 17 pages, revtex (aps, eqsecnum), submitted to PRD, April 199