Markov models for the evolution of duplicate genes, and microsatellites

Duplicate genes and microsatellites are two key sequences in the study of evolutionary genomics. Gene duplication has been identified as a central process driving functional change in genomes, since it creates functional redundancy in the genome and allows for subsequent mutation to occur in the absence of selective pressure. Microsatellites are rapidly evolving sequences which can be studied over much smaller timescales than most other sequences, and are thus key to the study of population demographics and forensic science. In this thesis we construct mathematical models for the evolution of duplicate genes, and microsatellites, respectively. We analyse the models in order to make scientific predictions, and derive the following novel results. We introduce and analyse a modified hazard function, which we use to investigate the preservation of gene duplicates. Further, we construct individual-level models, and present a framework for the extension to population-level models. Also, we construct mappings from mechanistically-motivated intuitive models for gene duplicate evolution, to less intuitive models, which have smaller state spaces and hence are more computationally tractable. Throughout this analysis, we make scientific predictions based on the properties of the models. We find that the pattern of gene duplicate preservation is more consistent with subfunctionalization than with neofunctionalization. This result is of particular scientific interest, since it is the opposite conclusion of earlier work in the gene duplication literature. ${Duplicate}$ ${genes}$ Several biological models exist for the evolution of a pair of duplicate genes after a duplication event, and it is believed that gene duplicates can evolve in different ways, according to one process, or a mix of processes. Subfunctionalization is a process under which the two duplicates can be preserved by dividing up the functions of the original gene between them. Here, we find that subfunctionalization is highly consistent with the pattern of gene duplicate preservation, in contrast to previous analysis in the literature. Another process important to gene duplicate evolution is neofunctionalization, under which both duplicates can be preserved when one copy mutates so as to produce some new beneficial function. Our analysis of neofunctionalization suggests that this process is not a significant contributor to the preservation of duplicates over the timescales during which regulatory subfunctionalization is resolved. Instead, it is likely that neofunctionalization occurs subsequent to previous subfunctionalization, which acts to preserve copies over the longer time frames required for rare beneficial mutations to have any significant probability of occurring. Analysis of genomic data using sub- and neofunctionalization models has thus far been relatively coarse-grained, with mathematical treatments usually focusing on the phenomenological features of gene duplicate evolution. In contrast, we develop mechanistically motivated Markov models, and fit directly to duplicate preservation data. We introduce a modified-cause-specific hazard function to analyse the preservation of gene duplicates. In the context of gene duplication, we refer to this as the pseudogenization rate, owing to the biological interpretation. We analyse the properties of the modified-cause-specific hazard rate in detail, including limit analysis of the general case, and discuss the shape properties of the specific case of the pseudogenization rate. Further, we extend our model for the evolution of a pair of gene duplicates to model a population of duplicate pairs, by modelling the birth of such pairs as a homogeneous Poisson process. We show that the age distribution of preserved duplicates follows an inhomogenous Poisson distribution, with its rate function depending on the individuallevel model. We then fit this distribution to count-data of surviving duplicates in the genomes of four animal species. Additionally, we extend the individual-level model to a model that includes the process of neofunctionalization, and next, to a model of subfunctionalization for families of gene duplicates. Finally, we map these intuitive models, to less intuitive but more computationally tractable models, and discuss a number of related computational considerations. ${Microsatellites}$ Microsatellites are repetitive regions of DNA where a short motif is repeated many times. Mutations in the number of repeat units occur frequently compared to point mutations and thus provide a useful source of genetic variation for studying recent events. Empirical studies have suggested that the rate of length-changing mutations due to slipped-strand mispairing may depend on the purity of the repeat units, i.e. how well they each match the motif. However, most studies that use microsatellite data are based on models that only track the number of repeat units. In order to address this gap, we introduce a series of models on a two-dimensional state-space (which are level-dependent quasi-birth-and-death processes) that track the length of the sequence as the level variable, and the number of interruptions (purity) as the phase variable. Our models account for the biological process of point mutation, and its observed effect on the rate of slipped-strand mispairing. We find that modelling microsatellite purity leads to some complications due to the nature of available data. In terms of the initial model, we discover what constitutes a state-dependent bias in the reporting of repeat sequences by Tandem Repeats Finder (or any similar software used to search whole-genomes for microsatellite sequences). Consequently, we construct a modified model such that all states fall into one of two categories - 'observable states', against which the reporting algorithm is unbiased, and 'unobservable states', which are never reported. We consider two approaches for treating the unobservable states, first to condition on the process being in the observable states, second to treat unobservable states as absorbing. Our initial analysis and underlying biological intuition suggest that transitions from the unobservable to observable states are very rare, and thus we ultimately treat the unobservable states as absorbing. Additionally, we extend the individual-level model to a population-level model by modelling the birth of microsatellites as a homogeneous Poisson process. We then derive the transient distribution of such model in terms of the individual-level process. This distribution has appropriate relative clock via the inclusion of point mutation. We fit this transient distribution to whole-genome derived sequence data, however we encounter some dificulties in the optimisation owing to the presence of many local optima. The standard approach for microsatellite models is to make the assumption that the empirical distribution is at equilibrium, and then to fit the stationary distribution to data. The key exception to this is the step-wise mutation model, which predicts infinite growth of the repeat number. Here we fit the above-mentioned transient distribution, and thus do not assume that the empirical distribution is at equilibrium. In contrast to the step-wise mutation model, our model does not predict infinite sequence lengths in the long run

The Climate-system Historical Forecast Project: providing open access to seasonal forecast ensembles from centers around the globe

Fil: Tompkins, Adrian M.. The Abdus Salam; ItaliaFil: Ortiz de Zarate, Maria Ines. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Centro de Investigaciones del Mar y la Atmósfera. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Centro de Investigaciones del Mar y la Atmósfera; Argentina. Centre National de la Recherche Scientifique; FranciaFil: Saurral, Ramiro Ignacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Centro de Investigaciones del Mar y la Atmósfera. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Centro de Investigaciones del Mar y la Atmósfera; Argentina. Centre National de la Recherche Scientifique; FranciaFil: Vera, Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Centro de Investigaciones del Mar y la Atmósfera. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Centro de Investigaciones del Mar y la Atmósfera; Argentina. Centre National de la Recherche Scientifique; FranciaFil: Saulo, Andrea Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Ministerio de Defensa. Secretaria de Planeamiento. Servicio Meteorológico Nacional; ArgentinaFil: Merryfield, William J.. Canadian Centre for Climate Modelling and Analysis; CanadáFil: Sigmond, Michael. Canadian Centre for Climate Modelling and Analysis; CanadáFil: Lee, Woo Sung. Canadian Centre for Climate Modelling and Analysis; CanadáFil: Baehr, Johanna. Universitat Hamburg; AlemaniaFil: Braun, Alain. Météo-France; FranciaFil: Amy Butler. National Ocean And Atmospheric Administration; Estados UnidosFil: Déqué, Michel. Météo-France; FranciaFil: Doblas Reyes, Francisco J.. Institució Catalana de Recerca i Estudis Avancats; España. Barcelona Supercomputing Center - Centro Nacional de Supercomputacion; EspañaFil: Gordon, Margaret. Met Office; Reino UnidoFil: Scaife, Adam A.. University of Exeter; Reino UnidoFil: Yukiko Imada. Japan Meteorological Agency. Meteorological Research Institute. Climate Research Department; JapónFil: Masayoshi Ishii. Japan Meteorological Agency. Meteorological Research Institute. Climate Research Department; JapónFil: Tomoaki Ose. Japan Meteorological Agency. Meteorological Research Institute. Climate Research Department; JapónFil: Kirtman, Ben. University of Miami; Estados UnidosFil: Kumar, Arun. National Ocean And Atmospheric Administration; Estados UnidosFil: Müller, Wolfgang A.. Max-Planck-Institut für Meteorologie; AlemaniaFil: Pirani, Anna. Université Paris-Saclay; FranciaFil: Stockdale, Tim. European Centre for Medium-Range Weather; Reino UnidoFil: Rixen, Michel. World Meteorological Organization. World Climate Research Programme; SuizaFil: Yasuda, Tamaki. Japan Meteorological Agency. Climate Prediction Division; Japó

女子短大生を対象としたウエイトコントロール教室の試み

We carried out weight control class from October 1993 to March 1994, to give a method of reasonable weight control and think it among women college students. The results are as follows; 1) At first 37 students attended, but 25 students were measured for the fundamental items. Only 2 students were continued to record weight, steps and foods for about six months. 2) The mean value of height, weight, Body Mass Index (BMI) were 158.8±4.0cm, 56.5±5.1kg, 23. 4±1.6 respectively. Forarm cirumference (left), upperarm circumference (left and right), upperarm circumference, fixed (right), the supersonic waves method (umbilical region) and back extension of the physical education students were significantly higher than the nutrition students. 3) Blood examination and routine urinalysis were within normal limit. 4) Among 25 students, 10 students had experience in diet. Indefinite complaints were 17 items in 27. The order of the dissatisfaction of figure of the students were the legs, the whole body, the weight, the waist, the hips, the breast. 5) The averge for 5 points in egogram was 11.0, Nuturing Parent (NP) was 13.4 the highest, Adult (A) and Critical Parent (CP) were 9.5 and 9.9 respectively. 6) The participation term at the weight control class, were 24 weeks (Case 1) and 18 weeks (Case 2). Weight of 1.2kg incresed in Case 1, and in Case 2 the weight did not change with some fluctuations during the term

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

CT-based dose-volume parameters of the rectum and late rectal complications in patients with cervical cancer treated with high-dose-rate intracavitary brachytherapy

Purpose: To evaluate the efficacy of CT-based dose-volume parameters of the rectum as the predictive factors for late rectal complications (LRC) in patients with cervical cancer treated with radiotherapy alone. \nMethods and Materials: Eighty-four patients treated with radiotherapy alone between January 2000 and December 2004 were retrospectively analyzed. All patients received the combination of external beam radiotherapy (EBRT) and high-dose-rate intracavitary brachytherapy (HDR-ICBT). The median total dose of EBRT was 50 Gy, consisting of whole pelvic irradiation and central shielding pelvic irradiation. The median total dose to point A in HDR-ICBT was 24 Gy in 4 fractions. HDR-ICBT was prescribed using X-ray based two-dimensional dosimetry and planning. Patients underwent CT scans of the pelvis with the applicators in place to generate three-dimensional dose distributions. The external contours of the rectum were delineated on the CT images, and the minimum doses delivered to 0.1cc, 1cc, 2cc, and 5cc of the most irradiated rectal volumes were determined from the dose-volume histgrams. The ICRU rectal reference point dose was derived from the conventional method. The doses in EBRT and ICBT were transformed to the biologically equivalent doses in 2 Gy fractions (EQD2) using a/B ratio of 3 Gy, and the total rectal doses for dose-volume parameters (D0.1cc, D1cc, D2cc, D5cc, and DICRU) were calculated. The correlation between the dose-volume parameters and the actuarial rate of LRC was analyzed.Results: The median follow-up duration for all patients was 46 months (range, 12-79 months). Twenty patients developed LRC (Grade 1: 12, Grade 2: 8). The 5-year actuarial rate of LRC was 27.4%. There was a statistically significant difference in D0.1cc, D1cc, D2cc, and D5cc between patients with and without LRC (p 60 Gy showed significantly greater incidence of LRC (p<0.001). When patients were grouped with DICRU, there was no significant difference in 5-year LRC rates among them.Conclusion: The present study suggests that CT-based dose-volume parameters may be good predictors of LRC in radiotherapy for cervical cancer.ABS/GEC-ESTRO 2008 World Congress of Bracheytherap