How Many Subpopulations is Too Many? Exponential Lower Bounds for Inferring Population Histories

Reconstruction of population histories is a central problem in population genetics. Existing coalescent-based methods, like the seminal work of Li and Durbin (Nature, 2011), attempt to solve this problem using sequence data but have no rigorous guarantees. Determining the amount of data needed to correctly reconstruct population histories is a major challenge. Using a variety of tools from information theory, the theory of extremal polynomials, and approximation theory, we prove new sharp information-theoretic lower bounds on the problem of reconstructing population structure -- the history of multiple subpopulations that merge, split and change sizes over time. Our lower bounds are exponential in the number of subpopulations, even when reconstructing recent histories. We demonstrate the sharpness of our lower bounds by providing algorithms for distinguishing and learning population histories with matching dependence on the number of subpopulations. Along the way and of independent interest, we essentially determine the optimal number of samples needed to learn an exponential mixture distribution information-theoretically, proving the upper bound by analyzing natural (and efficient) algorithms for this problem.Comment: 38 pages, Appeared in RECOMB 201

Planar digital nanoliter dispensing system based on thermocapillary actuation

We provide guidelines for the design and operation of a planar digital nanodispensing system based on thermocapillary actuation. Thin metallic microheaters embedded within a chemically patterned glass substrate are electronically activated to generate and control 2D surface temperature distributions which either arrest or trigger liquid flow and droplet formation on demand. This flow control is a consequence of the variation of a liquid’s surface tension with temperature, which is used to draw liquid toward cooler regions of the supporting substrate. A liquid sample consisting of several microliters is placed on a flat rectangular supply cell defined by chemical patterning. Thermocapillary switches are then activated to extract a slender fluid filament from the cell and to divide the filament into an array of droplets whose position and volume are digitally controlled. Experimental results for the power required to extract a filament and to divide it into two or more droplets as a function of geometric and operating parameters are in excellent agreement with hydrodynamic simulations. The capability to dispense ultralow volumes onto a 2D substrate extends the functionality of microfluidic devices based on thermocapillary actuation previously shown effective in routing and mixing nanoliter liquid samples on glass or silicon substrates

Neuronal deletion of the circadian clock gene Bmal1 induces cell-autonomous dopaminergic neurodegeneration

Circadian rhythm dysfunction is a hallmark of Parkinson disease (PD), and diminished expression of the core clock gene Bmal1 has been described in patients with PD. BMAL1 is required for core circadian clock function but also serves nonrhythmic functions. Germline Bmal1 deletion can cause brain oxidative stress and synapse loss in mice, and it can exacerbate dopaminergic neurodegeneration in response to the toxin MPTP. Here we examined the effect of cell type-specific Bmal1 deletion on dopaminergic neuron viability in vivo. We observed that global, postnatal deletion of Bmal1 caused spontaneous loss of tyrosine hydroxylase+ (TH+) dopaminergic neurons in the substantia nigra pars compacta (SNpc). This was not replicated by light-induced disruption of behavioral circadian rhythms and was not induced by astrocyte- or microglia-specific Bmal1 deletion. However, either pan-neuronal or TH neuron-specific Bmal1 deletion caused cell-autonomous loss of TH+ neurons in the SNpc. Bmal1 deletion did not change the percentage of TH neuron loss after α-synuclein fibril injection, though Bmal1-KO mice had fewer TH neurons at baseline. Transcriptomics analysis revealed dysregulation of pathways involved in oxidative phosphorylation and Parkinson disease. These findings demonstrate a cell-autonomous role for BMAL1 in regulating dopaminergic neuronal survival and may have important implications for neuroprotection in PD

Functional Crosstalk between Type I and II Interferon through the Regulated Expression of STAT1

Small "priming" quantities of type I interferon enhance cellular responses to type II interferon by maintaining basal levels of STAT1, explaining the observed crosstalk between these two cytokines

Influence of Primary Care Physician Availability and Socioeconomic Deprivation on Breast Cancer from 1988 to 2008: A Spatio-Temporal Analysis

Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer death among women in the United States. It is unclear how county-level primary care physician (PCP) availability and socioeconomic deprivation affect the spatial and temporal variation of breast cancer incidence and mortality.We used the 1988-2008 public-use county-based data from nine Surveillance, Epidemiology, and End Results (SEER) programs to analyze the temporal and spatial disparity of PCP availability and socioeconomic deprivation on early-stage incidence, advanced-stage incidence and breast cancer mortality. The spatio-temporal analysis was implemented by a novel structural additive modeling approach.Greater PCP availability was significantly associated with higher early-stage incidence, advanced-stage incidence and mortality during the entire study period while socioeconomic deprivation was significantly negatively associated with early-stage incidence, advanced-stage incidence, and mortality up to 1992. However, the observed influence of PCP availability and socioeconomic deprivation varied by county.We showed important associations of PCP availability and socioeconomic deprivation with the three breast cancer indicators. However, the effect of these associations varied over time and across counties. The association of PCP availability and socioeconomic deprivation was stronger in selected counties

A study of sertraline in dialysis (ASSertID) : a protocol for a pilot randomised controlled trial of drug treatment for depression in patients undergoing haemodialysis

© 2015 Friedli et al. Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise statedBACKGROUND: The prevalence of depression in people receiving haemodialysis is high with estimates varying between 20 and 40 %. There is little research on the effectiveness of antidepressants in dialysis patients with the few clinical trials suffering significant methodological issues. We plan to carry out a study to evaluate the feasibility of conducting a randomised controlled trial in patients on haemodialysis who have diagnosed Major Depressive Disorder.METHODS/DESIGN: The study has two phases, a screening phase and the randomised controlled trial. Patients will be screened initially with the Beck Depression Inventory to estimate the number of patients who score 16 or above. These patients will be invited to an interview with a psychiatrist who will invite those with a diagnosis of Major Depressive Disorder to take part in the trial. Consenting patients will be randomised to either Sertraline or placebo. Patients will be followed-up for 6 months. Demographic and clinical data will be collected at screening interview, baseline interview and 2 weeks, and every month (up to 6 months) after baseline. The primary outcome is to evaluate the feasibility of conducting a randomised, double blind, placebo pilot trial in haemodialysis patients with depression. Secondary outcomes include estimation of the variability in the outcome measures for the treatment and placebo arms, which will allow for a future adequately powered definitive trial. Analysis will primarily be descriptive, including the number of patients eligible for the trial, drug exposure of Sertraline in haemodialysis patients and the patient experience of participating in this trial.DISCUSSION: There is an urgent need for this research in the dialysis population because of the dearth of good quality and adequately powered studies. Research with renal patients is particularly difficult as they often have complex medical needs. This research will therefore not only assess the outcome of anti-depressants in haemodialysis patients with depression but also the process of running a randomised controlled trial in this population. Hence, the outputs of this feasibility study will be used to inform the design and methodology of a definitive study, adequately powered to determine the efficacy of anti-depressants in patient on haemodialysis with depression.TRIAL REGISTRATION: ISRCTN registry ISRCTN06146268 and EudraCT reference: 2012-000547-27.Peer reviewedFinal Published versio

Constitutive Activation of PrfA Tilts the Balance of Listeria monocytogenes Fitness Towards Life within the Host versus Environmental Survival

PrfA is a key regulator of Listeria monocytogenes pathogenesis and induces the expression of multiple virulence factors within the infected host. PrfA is post-translationally regulated such that the protein becomes activated upon bacterial entry into the cell cytosol. The signal that triggers PrfA activation remains unknown, however mutations have been identified (prfA* mutations) that lock the protein into a high activity state. In this report we examine the consequences of constitutive PrfA activation on L. monocytogenes fitness both in vitro and in vivo. Whereas prfA* mutants were hyper-virulent during animal infection, the mutants were compromised for fitness in broth culture and under conditions of stress. Broth culture prfA*-associated fitness defects were alleviated when glycerol was provided as the principal carbon source; under these conditions prfA* mutants exhibited a competitive advantage over wild type strains. Glycerol and other three carbon sugars have been reported to serve as primary carbon sources for L. monocytogenes during cytosolic growth, thus prfA* mutants are metabolically-primed for replication within eukaryotic cells. These results indicate the critical need for environment-appropriate regulation of PrfA activity to enable L. monocytogenes to optimize bacterial fitness inside and outside of host cells

Resources, Capabilities, and Routines in Public Organizations

States, state agencies, multilateral agencies, and other non-market actors are relatively under-studied in strategic management and organization science. While important contributions to the study of public actors have been made within the agency-theoretic and transaction-cost traditions, there is little research in political economy that builds on resource-based, dynamic capabilities, and behavioral approaches to the firm. Yet public organizations can be characterized as stocks of human and non-human resources, including routines and capabilities; they can possess excess capacity in these resources; and they may grow and diversify in predictable patterns according to behavioral and Penrosean logic. This paper shows how resource-based, dynamic capabilities, and behavioral approaches to understanding public agencies and organizations shed light on their nature and governance

Myths and misconceptions about hypnosis and suggestion: Separating fact and fiction

We present 21 prominent myths and misconceptions about hypnosis in order to promulgate accurate information and to highlight questions for future research. We argue that these myths and misconceptions have (a) fostered a skewed and stereotyped view of hypnosis among the lay public, (b) discouraged participant involvement in potentially helpful hypnotic interventions, and (c) impeded the exploration and application of hypnosis in scientific and practitioner communities. Myths reviewed span the view that hypnosis produces a trance or special state of consciousness and allied myths on topics related to hypnotic interventions; hypnotic responsiveness and the modification of hypnotic suggestibility; inducing hypnosis; and hypnosis and memory, awareness, and the experience of nonvolition. By demarcating myth from mystery and fact from fiction, and by highlighting what is known as well as what remains to be discovered, the science and practice of hypnosis can be advanced and grounded on a firmer empirical footing