SKELESIM: an extensible, general framework for population genetic simulation in R

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A Stochastic Approach to Shortcut Bridging in Programmable Matter

In a self-organizing particle system, an abstraction of programmable matter, simple computational elements called particles with limited memory and communication self-organize to solve system-wide problems of movement, coordination, and configuration. In this paper, we consider a stochastic, distributed, local, asynchronous algorithm for "shortcut bridging", in which particles self-assemble bridges over gaps that simultaneously balance minimizing the length and cost of the bridge. Army ants of the genus Eciton have been observed exhibiting a similar behavior in their foraging trails, dynamically adjusting their bridges to satisfy an efficiency trade-off using local interactions. Using techniques from Markov chain analysis, we rigorously analyze our algorithm, show it achieves a near-optimal balance between the competing factors of path length and bridge cost, and prove that it exhibits a dependence on the angle of the gap being "shortcut" similar to that of the ant bridges. We also present simulation results that qualitatively compare our algorithm with the army ant bridging behavior. Our work gives a plausible explanation of how convergence to globally optimal configurations can be achieved via local interactions by simple organisms (e.g., ants) with some limited computational power and access to random bits. The proposed algorithm also demonstrates the robustness of the stochastic approach to algorithms for programmable matter, as it is a surprisingly simple extension of our previous stochastic algorithm for compression.Comment: Published in Proc. of DNA23: DNA Computing and Molecular Programming - 23rd International Conference, 2017. An updated journal version will appear in the DNA23 Special Issue of Natural Computin

Manganese toxicity with ephedrone abuse manifesting as parkinsonism: a case report

Introduction: Neurologic consequences of manganese toxicity have been recognized since 1837. A new form of presumed manganese poisoning has been reported in drug addicted persons from Eastern Europe and the Baltic states who have intravenously injected self-prepared methcathinone hydrochloride (ephedrone), which is synthesized from pseudoephedrine hydrochloride using potassium permanganate as a potent oxidant. This clinical syndrome is under-recognized in Western Europe and there are no reported cases in the literature from Ireland. Case presentation: We report a 30-year-old Eastern European man who presented with a two-year history of gait disturbance. A neurological assessment revealed features of parkinsonism which included hypophonia, hypomimia, mild bradykinesia and rigidity with no resting tremor. He held his arms slightly abducted from his sides when walking, with a reduction in arm swing. Magnetic resonance imaging of his brain showed a high signal on T1 in the globus pallidus and serum manganese levels were raised. He had no response to levodopa. Conclusion: Manganism secondary to ephedrone abuse causing parkinsonism has emerged in Western Europe in recent years due to mass immigration and often remains unrecognized. This paper highlights the various features of this rare cause of parkinsonism and aids in its recognition and subsequent diagnosis. Neurologists in Western Europe will increasingly encounter such patients

A single nucleotide polymorphism in the Bax gene promoter affects transcription and influences retinal ganglion cell death

Pro-apoptotic Bax is essential for RGC (retinal ganglion cell) death. Gene dosage experiments in mice, yielding a single wild-type Bax allele, indicated that genetic background was able to influence the cell death phenotype. DBA/2JBax+/− mice exhibited complete resistance to nerve damage after 2 weeks (similar to Bax−/− mice), but 129B6Bax+/− mice exhibited significant cell loss (similar to wild-type mice). The different cell death phenotype was associated with the level of Bax expression, where 129B6 neurons had twice the level of endogenous Bax mRNA and protein as DBA/2J neurons. Sequence analysis of the Bax promoters between these strains revealed a single nucleotide polymorphism (T129B6 to CDBA/2J) at position −515. A 1.5- to 2.5-fold increase in transcriptional activity was observed from the 129B6 promoter in transient transfection assays in a variety of cell types, including RGC5 cells derived from rat RGCs. Since this polymorphism occurred in a p53 half-site, we investigated the requirement of p53 for the differential transcriptional activity. Differential transcriptional activity from either 129B6 or DBA/2J Bax promoters were unaffected in p53−/− cells, and addition of exogenous p53 had no further effect on this difference, thus a role for p53 was excluded. Competitive electrophoretic mobility-shift assays identified two DNA–protein complexes that interacted with the polymorphic region. Those forming Complex 1 bound with higher affinity to the 129B6 polymorphic site, suggesting that these proteins probably comprised a transcriptional activator complex. These studies implicated quantitative expression of the Bax gene as playing a possible role in neuronal susceptibility to damaging stimuli

Nasty Viruses, Costly Plasmids, Population Dynamics, and the Conditions for Establishing and Maintaining CRISPR-Mediated Adaptive Immunity in Bacteria

Clustered, Regularly Interspaced Short Palindromic Repeats (CRISPR) abound in the genomes of almost all archaebacteria and nearly half the eubacteria sequenced. Through a genetic interference mechanism, bacteria with CRISPR regions carrying copies of the DNA of previously encountered phage and plasmids abort the replication of phage and plasmids with these sequences. Thus it would seem that protection against infecting phage and plasmids is the selection pressure responsible for establishing and maintaining CRISPR in bacterial populations. But is it? To address this question and provide a framework and hypotheses for the experimental study of the ecology and evolution of CRISPR, I use mathematical models of the population dynamics of CRISPR-encoding bacteria with lytic phage and conjugative plasmids. The results of the numerical (computer simulation) analysis of the properties of these models with parameters in the ranges estimated for Escherichia coli and its phage and conjugative plasmids indicate: (1) In the presence of lytic phage there are broad conditions where bacteria with CRISPR-mediated immunity will have an advantage in competition with non-CRISPR bacteria with otherwise higher Malthusian fitness. (2) These conditions for the existence of CRISPR are narrower when there is envelope resistance to the phage. (3) While there are situations where CRISPR-mediated immunity can provide bacteria an advantage in competition with higher Malthusian fitness bacteria bearing deleterious conjugative plasmids, the conditions for this to obtain are relatively narrow and the intensity of selection favoring CRISPR weak. The parameters of these models can be independently estimated, the assumption behind their construction validated, and the hypotheses generated from the analysis of their properties tested in experimental populations of bacteria with lytic phage and conjugative plasmids. I suggest protocols for estimating these parameters and outline the design of experiments to evaluate the validity of these models and test these hypotheses

Genetics of height and risk of atrial fibrillation: A Mendelian randomization study.

BACKGROUND: Observational studies have identified height as a strong risk factor for atrial fibrillation, but this finding may be limited by residual confounding. We aimed to examine genetic variation in height within the Mendelian randomization (MR) framework to determine whether height has a causal effect on risk of atrial fibrillation. METHODS AND FINDINGS: In summary-level analyses, MR was performed using summary statistics from genome-wide association studies of height (GIANT/UK Biobank; 693,529 individuals) and atrial fibrillation (AFGen; 65,446 cases and 522,744 controls), finding that each 1-SD increase in genetically predicted height increased the odds of atrial fibrillation (odds ratio [OR] 1.34; 95% CI 1.29 to 1.40; p = 5 × 10-42). This result remained consistent in sensitivity analyses with MR methods that make different assumptions about the presence of pleiotropy, and when accounting for the effects of traditional cardiovascular risk factors on atrial fibrillation. Individual-level phenome-wide association studies of height and a height genetic risk score were performed among 6,567 European-ancestry participants of the Penn Medicine Biobank (median age at enrollment 63 years, interquartile range 55-72; 38% female; recruitment 2008-2015), confirming prior observational associations between height and atrial fibrillation. Individual-level MR confirmed that each 1-SD increase in height increased the odds of atrial fibrillation, including adjustment for clinical and echocardiographic confounders (OR 1.89; 95% CI 1.50 to 2.40; p = 0.007). The main limitations of this study include potential bias from pleiotropic effects of genetic variants, and lack of generalizability of individual-level findings to non-European populations. CONCLUSIONS: In this study, we observed evidence that height is likely a positive causal risk factor for atrial fibrillation. Further study is needed to determine whether risk prediction tools including height or anthropometric risk factors can be used to improve screening and primary prevention of atrial fibrillation, and whether biological pathways involved in height may offer new targets for treatment of atrial fibrillation

Extinction times in the subcritical stochastic SIS logistic epidemic

Many real epidemics of an infectious disease are not straightforwardly super- or sub-critical, and the understanding of epidemic models that exhibit such complexity has been identified as a priority for theoretical work. We provide insights into the near-critical regime by considering the stochastic SIS logistic epidemic, a well-known birth-and-death chain used to model the spread of an epidemic within a population of a given size $N$. We study the behaviour of the process as the population size $N$ tends to infinity. Our results cover the entire subcritical regime, including the "barely subcritical" regime, where the recovery rate exceeds the infection rate by an amount that tends to 0 as $N \to \infty$ but more slowly than $N^{-1/2}$. We derive precise asymptotics for the distribution of the extinction time and the total number of cases throughout the subcritical regime, give a detailed description of the course of the epidemic, and compare to numerical results for a range of parameter values. We hypothesise that features of the course of the epidemic will be seen in a wide class of other epidemic models, and we use real data to provide some tentative and preliminary support for this theory.Comment: Revised; 34 pages; 6 figure

Three-dimensional kinematic motion analysis of a daily activity drinking from a glass: a pilot study

BACKGROUND: Development of reliable and objective evaluation methods is required, particularly for natural and goal-oriented upper-extremity tasks. Three-dimensional imaging measurement techniques have turned out to be a powerful tool for a quantitative and qualitative assessment of multijoint movements. The purpose of this study was to develop and test a method of three-dimensional motion analysis for the activity "drinking from a glass" and describe the drinking task with kinematic variables in control subjects. METHODS: A protocol was developed for the drinking activity including the set-up of cameras and positions of the markers and the subject. The drinking task included reaching, forward transport with glass, drinking, back transport and returning the hand to the initial position. An optoelectronic system was used for the three-dimensional kinematic motion capture. Movement times, velocities, joint angles and interjoint coordination for shoulder and elbow were computed and analyzed for twenty control subjects. Test-retest consistency was evaluated for six subjects. RESULTS: The test protocol showed good consistency in test-retest. Phase definitions for the drinking task were defined and verified. Descriptive kinematic variables were obtained for movement times, positions, velocities and joint angles for shoulder and elbow joint. Interjoint coordination between shoulder and elbow joint in reaching phase showed a high correlation. CONCLUSION: This study provides a detailed description of the three-dimensional kinematic analysis of the drinking task. Our approach to investigate and analyze a goal-oriented daily activity has a great clinical potential. Consequently, the next step is to use and test this protocol on persons with impairments and disabilities from upper extremities

Transition probabilities for general birth-death processes with applications in ecology, genetics, and evolution

A birth-death process is a continuous-time Markov chain that counts the number of particles in a system over time. In the general process with $n$ current particles, a new particle is born with instantaneous rate $\lambda_n$ and a particle dies with instantaneous rate $\mu_n$. Currently no robust and efficient method exists to evaluate the finite-time transition probabilities in a general birth-death process with arbitrary birth and death rates. In this paper, we first revisit the theory of continued fractions to obtain expressions for the Laplace transforms of these transition probabilities and make explicit an important derivation connecting transition probabilities and continued fractions. We then develop an efficient algorithm for computing these probabilities that analyzes the error associated with approximations in the method. We demonstrate that this error-controlled method agrees with known solutions and outperforms previous approaches to computing these probabilities. Finally, we apply our novel method to several important problems in ecology, evolution, and genetics