Mutation Induced Extinction in Finite Populations: Lethal Mutagenesis and Lethal Isolation

Reproduction is inherently risky, in part because genomic replication can introduce new mutations that are usually deleterious toward fitness. This risk is especially severe for organisms whose genomes replicate “semi-conservatively,” e.g. viruses and bacteria, where no master copy of the genome is preserved. Lethal mutagenesis refers to extinction of populations due to an unbearably high mutation rate (U), and is important both theoretically and clinically, where drugs can extinguish pathogens by increasing their mutation rate. Previous theoretical models of lethal mutagenesis assume infinite population size (N). However, in addition to high U, small N can accelerate extinction by strengthening genetic drift and relaxing selection. Here, we examine how the time until extinction depends jointly on N and U. We first analytically compute the mean time until extinction (τ) in a simplistic model where all mutations are either lethal or neutral. The solution motivates the definition of two distinct regimes: a survival phase and an extinction phase, which differ dramatically in both how τ scales with N and in the coefficient of variation in time until extinction. Next, we perform stochastic population-genetics simulations on a realistic fitness landscape that both (i) features an epistatic distribution of fitness effects that agrees with experimental data on viruses and (ii) is based on the biophysics of protein folding. More specifically, we assume that mutations inflict fitness penalties proportional to the extent that they unfold proteins. We find that decreasing N can cause phase transition-like behavior from survival to extinction, which motivates the concept of “lethal isolation.” Furthermore, we find that lethal mutagenesis and lethal isolation interact synergistically, which may have clinical implications for treating infections. Broadly, we conclude that stably folded proteins are only possible in ecological settings that support sufficiently large populations.Chemistry and Chemical Biolog

The Milky Way bar/bulge in proper motions: a 3D view from VIRAC & Gaia

© 2019 The Author(s) Published by Oxford University Press on behalf of the Royal Astronomical Society.We have derived absolute proper motions of the entire Galactic bulge region from VIRAC and Gaia. We present these as both integrated on-sky maps and, after isolating standard candle red clump (RC) stars, as a function of distance using RC magnitude as a proxy. These data provide a new global, 3-dimensional view of the Milky Way barred bulge kinematics. We find a gradient in the mean longitudinal proper motion, $\mu_l$, between the different sides of the bar, which is sensitive to the bar pattern speed. The split RC has distinct proper motions and is colder than other stars at similar distance. The proper motion correlation map has a quadrupole pattern in all magnitude slices showing no evidence for a separate, more axisymmetric inner bulge component. The line-of-sight integrated kinematic maps show a high central velocity dispersion surrounded by a more asymmetric dispersion profile. $\sigma_{\mu_l} / \sigma_{\mu_b}$ is smallest, $\sim1.1$, near the minor axis and reaches $\sim1.4$ near the disc plane. The integrated $$ pattern signals a superposition of bar rotation and internal streaming motion, with the near part shrinking in latitude and the far part expanding. To understand and interpret these remarkable data, we compare to a made-to-measure barred dynamical model, folding in the VIRAC selection function to construct mock maps. We find that our model of the barred bulge, with a pattern speed of 37.5 $\mathrm{km \, s^{-1} \, kpc^{-1}}$, is able to reproduce all observed features impressively well. Dynamical models like this will be key to unlocking the full potential of these data.Peer reviewe

Membrane-Bound Steel Factor Maintains a High Local Concentration for Mouse Primordial Germ Cell Motility, and Defines the Region of Their Migration

Steel factor, the protein product of the Steel locus in the mouse, is a multifunctional signal for the primordial germ cell population. We have shown previously that its expression accompanies the germ cells during migration to the gonads, forming a “travelling niche” that controls their survival, motility, and proliferation. Here we show that these functions are distributed between the alternatively spliced membrane-bound and soluble forms of Steel factor. The germ cells normally migrate as individuals from E7.5 to E11.5, when they aggregate together in the embryonic gonads. Movie analysis of Steel-dickie mutant embryos, which make only the soluble form, at E7.5, showed that the germ cells fail to migrate normally, and undergo “premature aggregation” in the base of the allantois. Survival and directionality of movement is not affected. Addition of excess soluble Steel factor to Steel-dickie embryos rescued germ cell motility, and addition of Steel factor to germ cells in vitro showed that a fourfold higher dose was required to increase motility, compared to survival. These data show that soluble Steel factor is sufficient for germ cell survival, and suggest that the membrane-bound form provides a higher local concentration of Steel factor that controls the balance between germ cell motility and aggregation. This hypothesis was tested by addition of excess soluble Steel factor to slice cultures of E11.5 embryos, when migration usually ceases, and the germ cells aggregate. This reversed the aggregation process, and caused increased motility of the germ cells. We conclude that the two forms of Steel factor control different aspects of germ cell behavior, and that membrane-bound Steel factor controls germ cell motility within a “motility niche” that moves through the embryo with the germ cells. Escape from this niche causes cessation of motility and death by apoptosis of the ectopic germ cells

Disputed Paraphilia Diagnoses and Legal Decision Making: A Case Law Survey of Paraphilia NOS, Nonconsent

Paraphilia diagnoses applied in forensic settings are an ongoing subject of debate among psycholegal professionals and scholars. Disagreements pertain to both means-related issues having to do with issues of diagnostic reliability and validity, and ends-related issues regarding the consequences inherent to the legal contexts in which the diagnoses arise. To provide a fresh outlook on some of the issues, the present study entailed a systematic survey of U.S. case law to investigate the history, extent, and nature of forensic uses of a controversial paraphilia diagnosis, paraphilia not otherwise specified, nonconsent. Descriptive analyses revealed that use of the diagnosis, which occurred almost exclusively in adult sexually violent predator cases, increased substantially over the past decade, with cases in 3 states accounting for over 2/3 of the total observed prevalence rate. In the majority of cases examined in detail, the support that evaluators relied upon in making the diagnosis was either not clearly described or behaviorally inferential in nature, and the diagnosis was often accompanied by other mental and personality disorder diagnoses. An opposing expert was observed in more than half of the cases, approximately 1/3 of whom noted the debate surrounding the diagnosis and nearly 2/3 of whom opined that there was insufficient evidentiary support for the diagnosis in the case at bar. Finally, all courts that reached the issue of the admissibility of the diagnosis between 2008 and 2011 admitted it, and most courts also found it sufficient to support classifying an individual as a sexually violent predator

Plakoglobin is required for maintenance of the cortical actin skeleton in early Xenopus embryos and for cdc42-mediated wound healing

Early Xenopus embryos are large, and during the egg to gastrula stages, when there is little extracellular matrix, the cytoskeletons of the individual blastomeres are thought to maintain their spherical architecture and provide scaffolding for the cellular movements of gastrulation. We showed previously that depletion of plakoglobin protein during the egg to gastrula stages caused collapse of embryonic architecture. Here, we show that this is due to loss of the cortical actin skeleton after depletion of plakoglobin, whereas the microtubule and cytokeratin skeletons are still present. As a functional assay for the actin skeleton, we show that wound healing, an actin-based behavior in embryos, is also abrogated by plakoglobin depletion. Both wound healing and the amount of cortical actin are enhanced by overexpression of plakoglobin. To begin to identify links between plakoglobin and the cortical actin polymerization machinery, we show here that the Rho family GTPase cdc42, is required for wound healing in the Xenopus blastula. Myc-tagged cdc42 colocalizes with actin in purse-strings surrounding wounds. Overexpression of cdc42 dramatically enhances wound healing, whereas depletion of maternal cdc42 mRNA blocks it. In combinatorial experiments we show that cdc42 cannot rescue the effects of plakoglobin depletion, showing that plakoglobin is required for cdc42-mediated cortical actin assembly during wound healing. However, plakoglobin does rescue the effect of cdc42 depletion, suggesting that cdc42 somehow mediates the distribution or function of plakoglobin. Depletion of α-catenin does not remove the cortical actin skeleton, showing that plakoglobin does not mediate its effect by its known linkage through α-catenin to the actin skeleton. We conclude that in Xenopus, the actin skeleton is a major determinant of cell shape and overall architecture in the early embryo, and that plakoglobin plays an essential role in the assembly, maintenance, or organization of this cortical actin

Perception of dynamic Glass patterns

AbstractIn the mammalian brain, form and motion are processed through two distinct pathways at early stages of visual processing. However, recent evidence suggests that these two pathways may interact. Here we used dynamic Glass patterns, which have been previously shown to create the perception of coherent motion in humans, despite containing no motion coherence. Glass patterns are static stimuli that consist of randomly positioned dot pairs that are integrated spatially to create the perception of a global form, whereas dynamic Glass patterns consist of several independently generated static Glass patterns presented sequentially. In the current study, we measured the detection threshold of five types of dynamic Glass patterns and compared the rank order of the detection thresholds with those found for static Glass patterns and real motion patterns (using random dot stimuli). With both the static Glass patterns and dynamic Glass patterns, detection thresholds were lowest for concentric and radial patterns and highest for horizontal patterns. We also found that vertical patterns were better detected than horizontal patterns, consistent with prior evidence of a “horizontal effect” in the perception of natural scene images. With real motion, detection thresholds were equivalent across all patterns, with the exception of higher thresholds for spiral patterns. Our results suggest that dynamic Glass patterns are processed primarily as form prior to input into the motion system

Temporal summation of global form signals in dynamic Glass patterns

AbstractThe ability to perceive complex objects in the environment requires that the visual system integrate local form information into global shapes. Glass patterns (GPs) are stimuli that are commonly used to study this integration process. GPs consist of randomly positioned dot-pairs oriented in a coherent way to create a global form. When multiple GPs are presented sequentially, observers report a percept of illusory coherent motion and have lower detection thresholds relative to a single presentation GPs. The percept of illusory motion has been attributed to the visual system interpreting the dot-pairs in GPs as motion streaks. However, it remains unclear why dynamic GPs are detected at lower thresholds than static GPs. Two main differences exist between static and dynamic GPs: (a) dynamic GPs contain multiple presentations of global form signals compared to a single presentation in static GPs and (b) dynamic GPs have a greater temporal frequency than static GPs. Here we investigated which of these two factors contributed to the heightened sensitivities for dynamic GPs. We systematically varied the number of unique GPs and the rate at which each unique frame is presented (i.e., temporal frequency). The results show that, within the range of temporal frequency used, the primary influence on detection thresholds was the number of unique frames. These results suggest that the improved detection sensitivities can be driven by a mechanism of temporal summation of global form

The contribution of nonrigid motion and shape information to object perception in pigeons and humans

The ability to perceive and recognize objects is essential to many animals, including humans. Until recently, models of object recognition have primarily focused on static cues, such as shape, but more recent research is beginning to show that motion plays an important role in object perception. Most studies have focused on rigid motion, a type of motion most often associated with inanimate objects. In contrast, nonrigid motion is often associated with biological motion and is therefore ecologically important to visually dependent animals. In this study, we examined the relative contribution of nonrigid motion and shape to object perception in humans and pigeons, two species that rely extensively on vision. Using a parametric morphing technique to systematically vary nonrigid motion and three-dimensional shape information, we found that both humans and pigeons were able to rely solely on either shape or nonrigid motion information to identify complex objects when one of the two cues was degraded. Humans and pigeons also showed similar 80% accuracy thresholds when the information from both shape and motion cues were degraded. We argue that the use of nonrigid motion for object perception is evolutionarily important and should be considered in general theories of vision at least with respect to visually sophisticated animals

Towards system redesign: An exploratory analysis of neurodivergent traits in a childhood population referred for autism assessment

Background: Children’s health services in many countries are moving from single condition diagnostic silo assessments to considering neurodevelopment in a more holistic sense. There has been increasing recognition of the importance of clinical overlap and co-occurrence of different neurotypes when assessing neurodivergent children. Using a cross-sectional service evaluation design, we investigated the overlap of neurodivergences in a cohort of children referred for autism assessment, focusing on motor, learning, and attention/activity level domains. We aimed to determine what proportion of children in a cohort referred for an autism assessment showed traits of additional neurodivergences, and what proportion were further investigated. Methods: We evaluated anonymised medical records of children aged between two and 17 years referred for autism assessment. We used validated questionnaires to assess for neurodivergent traits. A weighted scoring system was developed to determine traits in each neurodevelopmental domain and a score above the median was considered to indicate a neurodivergent trait. Evidence of further investigations were recorded. We then examined the relationships between autism traits and traits of additional neurodivergence. Results: 114 participants were included for evaluation. 62.3% (n = 71) had completed questionnaires for analysis. Of these, 71.8% (n = 51) scored greater than the median for at least one additional neurotype, indicating the presence of other neurodivergent traits, and 88.7% (n = 64) attracted a diagnosis of autism. Only 26.3% of children with evidence of additional neurotypes were further investigated beyond their autism assessment. Conclusions: Our results demonstrate the extensive overlap between additional neurodivergent traits in a population of children referred with suspected autism and show that only a small proportion were further investigated. The use of standardised questionnaires to uncover additional neurodivergences may have utility in improving the holistic nature of neurodevelopmental assessments