Clonal Interference, Multiple Mutations, and Adaptation in Large Asexual Populations

Two important problems affect the ability of asexual populations to accumulate beneficial mutations, and hence to adapt. First, clonal interference causes some beneficial mutations to be outcompeted by more-fit mutations which occur in the same genetic background. Second, multiple mutations occur in some individuals, so even mutations of large effect can be outcompeted unless they occur in a good genetic background which contains other beneficial mutations. In this paper, we use a Monte Carlo simulation to study how these two factors influence the adaptation of asexual populations. We find that the results depend qualitatively on the shape of the distribution of the effects of possible beneficial mutations. When this distribution falls off slower than exponentially, clonal interference alone reasonably describes which mutations dominate the adaptation, although it gives a misleading picture of the evolutionary dynamics. When the distribution falls off faster than exponentially, an analysis based on multiple mutations is more appropriate. Using our simulations, we are able to explore the limits of validity of both of these approaches, and we explore the complex dynamics in the regimes where neither are fully applicable.Comment: 24 pages, 5 figure

Increasing Employee Awareness of the Signs and Symptoms of Heart Attack and the Need to Use 911 in a State Health Department

INTRODUCTION: Early recognition of the signs and symptoms of a heart attack can lead to reduced morbidity and mortality. METHODS: A workplace intervention was conducted among 523 Montana state health department employees in 2003 to increase awareness of the signs and symptoms of heart attack and the need to use 911. All employees received an Act in Time to Heart Attack Signs brochure and wallet card with their paychecks. Act in Time posters were placed in key workplace areas. A weekly e-mail message, including a contest entry opportunity addressing the signs and symptoms of heart attack, was sent to all employees. Baseline and follow-up telephone surveys were conducted to evaluate intervention effectiveness. RESULTS: Awareness of heart attack signs and symptoms and the need to call 911 increased significantly among employees from baseline to follow-up: pain or discomfort in the jaw, neck, or back (awareness increased from 69% to 91%); feeling weak, light-headed, or faint (awareness increased from 79% to 89%); call 911 if someone is having a heart attack or stroke (awareness increased from 84% to 90%). Awareness of chest pain, pain or discomfort in the arms or shoulders, and shortness of breath were more than 90% at baseline and did not increase significantly at follow-up. At baseline, 69% of respondents correctly reported five or more of the signs and symptoms of heart attack; 89% reported correctly at follow-up. CONCLUSION: This low-cost workplace intervention increased awareness of the signs and symptoms of heart attack and the need to call 911

Genes in the postgenomic era

We outline three very different concepts of the gene - 'instrumental', 'nominal', and 'postgenomic'. The instrumental gene has a critical role in the construction and interpretation of experiments in which the relationship between genotype and phenotype is explored via hybridization between organisms or directly between nucleic acid molecules. It also plays an important theoretical role in the foundations of disciplines such as quantitative genetics and population genetics. The nominal gene is a critical practical tool, allowing stable communication between bioscientists in a wide range of fields grounded in well-defined sequences of nucleotides, but this concept does not embody major theoretical insights into genome structure or function. The post-genomic gene embodies the continuing project of understanding how genome structure supports genome function, but with a deflationary picture of the gene as a structural unit. This final concept of the gene poses a significant challenge to conventional assumptions about the relationship between genome structure and function, and between genotype and phenotype

Protocol of the Cognitive Health in Ageing Register: Investigational, Observational and Trial Studies in Dementia Research (CHARIOT): Prospective Readiness cOhort (PRO) SubStudy

The Cognitive Health in Ageing Register: Investigational, Observational and Trial Studies in Dementia Research (CHARIOT): Prospective Readiness cOhort (PRO) SubStudy (CPSS), sponsored by Janssen Pharmaceutical Research & Development LLC, is an Alzheimer's disease (AD) biomarker enriched observational study that began 3 July 2015 CPSS aims to identify and validate determinants of AD, alongside cognitive, functional and biological changes in older adults with or without detectable evidence of AD pathology at baseline. CPSS is a dual-site longitudinal cohort (3.5 years) assessed quarterly. Cognitively normal participants (60-85 years) were recruited across Greater London and Edinburgh. Participants are classified as high, medium (amnestic or non-amnestic) or low risk for developing mild cognitive impairment-Alzheimer's disease based on their Repeatable Battery for the Assessment of Neuropsychological Status performance at screening. Additional AD-related assessments include: a novel cognitive composite, the Global Preclinical Alzheimer's Cognitive Composite, brain MRI and positron emission tomography and cerebrospinal fluid analysis. Lifestyle, other cognitive and functional data, as well as biosamples (blood, urine, and saliva) are collected. Primarily, study analyses will evaluate longitudinal change in cognitive and functional outcomes. Annual interim analyses for descriptive data occur throughout the course of the study, although inferential statistics are conducted as required. CPSS received ethical approvals from the London-Central Research Ethics Committee (15/LO/0711) and the Administration of Radioactive Substances Advisory Committee (RPC 630/3764/33110) The study is at the forefront of global AD prevention efforts, with frequent and robust sampling of the well-characterised cohort, allowing for detection of incipient pathophysiological, cognitive and functional changes that could inform therapeutic strategies to prevent and/or delay cognitive impairment and dementia. Dissemination of results will target the scientific community, research participants, volunteer community, public, industry, regulatory authorities and policymakers. On study completion, and following a predetermined embargo period, CPSS data are planned to be made accessible for analysis to facilitate further research into the determinants of AD pathology, onset of symptomatology and progression. The CHARIOT:PRO SubStudy is registered with clinicaltrials.gov (NCT02114372). Notices of protocol modifications will be made available through this trial registry. [Abstract copyright: © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Precision medicine in cats:novel niemann-pick type C1 diagnosed by whole-genome sequencing

State-of-the-art health care includes genome sequencing of the patient to identify genetic variants that contribute to either the cause of their malady or variants that can be targeted to improve treatment. The goal was to introduce state-of-the-art health care to cats using genomics and a precision medicine approach. To test the feasibility of a precision medicine approach in domestic cats, a single cat that presented to the University of Missouri, Veterinary Health Center with an undiagnosed neurologic disease was whole-genome sequenced. The DNA variants from the cat were compared to the DNA variant database produced by the 99 Lives Cat Genome Sequencing Consortium. Approximately 25× genomic coverage was produced for the cat. A predicted p.H441P missense mutation was identified in NPC1, the gene causing Niemann-Pick type C1 on cat chromosome D3.47456793 caused by an adenine-to-cytosine transversion, c.1322A>C. The cat was homozygous for the variant. The variant was not identified in any other 73 domestic and 9 wild felids in the sequence database or 190 additionally genotyped cats of various breeds. The successful effort suggested precision medicine is feasible for cats and other undiagnosed cats may benefit from a genomic analysis approach. The 99 Lives DNA variant database was sufficient but would benefit from additional cat sequences. Other cats with the mutation may be identified and could be introduced as a new biomedical model for NPC1. A genetic test could eliminate the disease variant from the population

Overview of the TRYAD Project: A Fleet of Two 6U CubeSats for Research on Terrestrial Gamma Ray Flashes

The fleet of two 6U CubeSats of the Terrestrial RaYs Analysis and Detection – TRYAD – project will explore the spatial structure of Terrestrial Gamma Ray Flashes produced by thunderstorms. At the core of this NSF supported project, is the ability to obtain simultaneous data from two CubeSats and VLF ground stations. Time synchronization is vital for correlating data from the three sources. The project is a collaboration between the University of Alabama in Huntsville (UAH) and Auburn University (AU). Also involved in the project are the NASA Goddard Space Flight Center and the Sci_Zone company. The UAH team (Drs. M. Briggs and P. Jenke) is in charge of developing the science instrument, determining the science data collection activities during flight, analyzing these data and publishing the results. The AU team (Drs. J-M Wersinger, M. Fogle, S. Biaz, and D. Harris) is in charge of developing the CubeSat platforms carrying the science instrument, of securing all interfaces, obtaining a launch, operating the satellites during flight, obtaining and forwarding data to UAH. NASA GSFC scientists and engineers, under the direction of Dr. G. de Nolfo are developing the gamma ray detector. Mr. A. Santangelo, CTO of Sci_Zone is providing and implementing the Linkstar radios (a duplex and a simplex) that will give access to science data in real time over 40% of the orbit as well as a beacon everywhere along the orbit. The Linkstar radios are communicating through the network of Globalstar satellites. Mission success requires the ability to modify and control the separation of the two satellites along a common orbit. To this effect, the project is using differential drag. The two satellites, TRYAD 1 and TRYAD 2 are equipped with adjustable fins making them look like darts. Fin angle with the body of the satellites is adjusted through commands from the ground changing ionospheric drag on the satellites. The satellite with the largest drag loses more altitude than the other one, goes to a lower orbit and thus increases its speed. This speed difference allows for satellite separation modifications and control. At end of mission, both satellites’ fins are put into maximum drag configuration shortening the satellites’ lifetime in space. The satellite development is done by undergraduate students organized in technical and management teams. Each team has a lead and a deputy. New recruits are added twice a year, join a team and are trained by the senior members of their team. The project emphasizes good management practices and uses the NASA Systems Engineering approach. Most of the elements of the satellites are designed and built by the student teams. The only significant elements purchased are the Linkstar radios and DHV solar panels. The satellites carry over 100 sensors. The central computing unit is a BeagleBone Black (BBB) supplemented by two micro-controllers. Thermal control of satellite elements is obtained by radiative coupling with Earth through one of the large sides of the satellites and by heating elements controlled by the BBB

(2006-2007) Assembly Resolution 08: Recognizing The City of Austin, Capital Metro, AT&T, and Cingular for Working With Orange Jackets to Promote Safety in West Campus by Creating Emergency Callboxes for Students

Governmen

Sleep and circadian defects in a Drosophila model of mitochondrial encephalomyopathy

Mitochondrial encephalomyopathies (ME) are complex, incurable diseases characterized by severe bioenergetic distress that can affect the function of all major organ systems but is especially taxing to neuromuscular tissues. Animal models of MEs are rare, but the Drosophila ATP61 mutant is a stable, well-characterized genetic line that accurately models progressive human mitochondrial diseases such as Maternally-Inherited Leigh Syndrome (MILS), Neuropathy, Ataxia, and Retinitis Pigmentosa (NARP), and Familial Bilateral Striatal Necrosis (FBSN). While it is established that this model exhibits important hallmarks of ME, including excess cellular and mitochondrial reactive oxygen species, shortened lifespan, muscle degeneration, and stress-induced seizures, it is unknown whether it exhibits defects in sleep or circadian function. This is a clinically relevant question, as many neurological and neurodegenerative diseases are characterized by such disturbances, which can exacerbate other symptoms and worsen quality of life. Since Drosophila is highly amenable to sleep and circadian studies, we asked whether we could detect disease phenotypes in the circadian behaviors of ATP61. Indeed, we found that day-time and night-time activity and sleep are altered through disease progression, and that circadian patterns are disrupted at both the behavioral and neuronal levels. These results establish ATP61 as an important model of sleep and circadian disruption in ME that can be studied mechanistically at the molecular, cellular, and behavioral level to uncover underlying pathophysiology and test novel therapies. Keywords: Mitochondrial disease, Neurodegenerative disease, Drosophil

Multispectral UAS Data Accuracy for Different Radiometric Calibration Methods

Unmanned aircraft systems (UAS) allow us to collect aerial data at high spatial and temporal resolution. Raw images are taken along a predetermined flight path and processed into a single raster file covering the entire study area. Radiometric calibration using empirical or manufacturer methods is required to convert raw digital numbers into reflectance and to ensure data accuracy. The performance of five radiometric calibration methods commonly used was investigated in this study. Multispectral imagery was collected using a Parrot Sequoia camera. No method maximized data accuracy in all bands. Data accuracy was higher when the empirical calibration was applied to the processed raster rather than the raw images. Data accuracy achieved with the manufacturer-recommended method was comparable to the one achieved with the best empirical method. Radiometric error in each band varied linearly with pixel radiometric values. Smallest radiometric errors were obtained in the red-edge and near-infrared (NIR) bands. Accuracy of the composite indices was higher for the pixels representing a dense vegetative cover in comparison to a lighter cover or bare soil. Results provided a better understanding of the advantages and limitations of existing radiometric calibration methods as well as the impact of the radiometric error on data quality. The authors recommend that researchers evaluate the performance of their radiometric calibration before analyzing UAS imagery and interpreting the results