Concurrent Computing with Shared Replicated Memory

The behavioural theory of concurrent systems states that any concurrent system can be captured by a behaviourally equivalent concurrent Abstract State Machine (cASM). While the theory in general assumes shared locations, it remains valid, if different agents can only interact via messages, i.e. sharing is restricted to mailboxes. There may even be a strict separation between memory managing agents and other agents that can only access the shared memory by sending query and update requests to the memory agents. This article is dedicated to an investigation of replicated data that is maintained by a memory management subsystem, whereas the replication neither appears in the requests nor in the corresponding answers. We show how the behaviour of a concurrent system with such a memory management can be specified using concurrent communicating ASMs. We provide several refinements of a high-level ground model addressing different replication policies and internal messaging between data centres. For all these refinements we analyse their effects on the runs such that decisions concerning the degree of consistency can be consciously made.Comment: 23 page

Population size and decadal trends of three penguin species nesting at Signy Island, South Orkney Islands

We report long-term changes in population size of three species of sympatrically breeding pygoscelid penguins: Adélie (Pygoscelis adeliae), chinstrap (Pygoscelis antarctica) and gentoo (Pygoscelis papua ellsworthii) over a 38 year period at Signy Island, South Orkney Islands, based on annual counts from selected colonies and decadal all-island systematic counts of occupied nests. Comparing total numbers of breeding pairs over the whole island from 1978/79 to 2015/16 revealed varying fortunes: gentoo penguin pairs increased by 255%, (3.5% per annum), chinstrap penguins declined by 68% (-3.6% per annum) and Adélie penguins declined by 42% (-1.5% per annum). The chinstrap population has declined steadily over the last four decades. In contrast, Adélie and gentoo penguins have experienced phases of population increase and decline. Annual surveys of selected chinstrap and Adélie colonies produced similar trends from those revealed by island-wide surveys, allowing total island population trends to be inferred relatively well. However, while the annual colony counts of chinstrap and Adélie penguins showed a trend consistent in direction with the results from all-island surveys, the magnitude of estimated population change was markedly different between colony wide and all island counts. Annual population patterns suggest that pair numbers in the study areas partly reflect immigration and emigration of nesting birds between different parts of the island. Breeding success for all three species remained broadly stable over time in the annually monitored colonies. Breeding success rates in gentoo and chinstrap penguins were strongly correlated, despite the differing trends in population size. This study shows the importance of effective, standardised monitoring to accurately determine long-term population trajectories. Our results indicate significant declines in the Adélie and chinstrap penguin populations at Signy Island over the last five decades, and a gradual increase in gentoo breeding pairs

Predictive modelling of Ross River virus notifications in southeastern Australia.

Ross River virus (RRV) is a mosquito-borne virus endemic to Australia. The disease, marked by arthritis, myalgia and rash, has a complex epidemiology involving several mosquito species and wildlife reservoirs. Outbreak years coincide with climatic conditions conducive to mosquito population growth. We developed regression models for human RRV notifications in the Mildura Local Government Area, Victoria, Australia with the objective of increasing understanding of the relationships in this complex system, providing trigger points for intervention and developing a forecast model. Surveillance, climatic, environmental and entomological data for the period July 2000-June 2011 were used for model training then forecasts were validated for July 2011-June 2015. Rainfall and vapour pressure were the key factors for forecasting RRV notifications. Validation of models showed they predicted RRV counts with an accuracy of 81%. Two major RRV mosquito vectors (Culex annulirostris and Aedes camptorhynchus) were important in the final estimation model at proximal lags. The findings of this analysis advance understanding of the drivers of RRV in temperate climatic zones and the models will inform public health agencies of periods of increased risk

Establishing the precise evolutionary history of a gene improves prediction of disease-causing missense mutations

PURPOSE: Predicting the phenotypic effects of mutations has become an important application in clinical genetic diagnostics. Computational tools evaluate the behavior of the variant over evolutionary time and assume that variations seen during the course of evolution are probably benign in humans. However, current tools do not take into account orthologous/paralogous relationships. Paralogs have dramatically different roles in Mendelian diseases. For example, whereas inactivating mutations in the NPC1 gene cause the neurodegenerative disorder Niemann-Pick C, inactivating mutations in its paralog NPC1L1 are not disease-causing and, moreover, are implicated in protection from coronary heart disease. METHODS: We identified major events in NPC1 evolution and revealed and compared orthologs and paralogs of the human NPC1 gene through phylogenetic and protein sequence analyses. We predicted whether an amino acid substitution affects protein function by reducing the organism’s fitness. RESULTS: Removing the paralogs and distant homologs improved the overall performance of categorizing disease-causing and benign amino acid substitutions. CONCLUSION: The results show that a thorough evolutionary analysis followed by identification of orthologs improves the accuracy in predicting disease-causing missense mutations. We anticipate that this approach will be used as a reference in the interpretation of variants in other genetic diseases as well. Genet Med 18 10, 1029–1036

Colon cancer associated genes exhibit signatures of positive selection at functionally significant positions

Background Cancer, much like most human disease, is routinely studied by utilizing model organisms. Of these model organisms, mice are often dominant. However, our assumptions of functional equivalence fail to consider the opportunity for divergence conferred by ~180 Million Years (MY) of independent evolution between these species. For a given set of human disease related genes, it is therefore important to determine if functional equivalency has been retained between species. In this study we test the hypothesis that cancer associated genes have different patterns of substitution akin to adaptive evolution in different mammal lineages. Results Our analysis of the current literature and colon cancer databases identified 22 genes exhibiting colon cancer associated germline mutations. We identified orthologs for these 22 genes across a set of high coverage (>6X) vertebrate genomes. Analysis of these orthologous datasets revealed significant levels of positive selection. Evidence of lineage-specific positive selection was identified in 14 genes in both ancestral and extant lineages. Lineage-specific positive selection was detected in the ancestral Euarchontoglires and Hominidae lineages for STK11, in the ancestral primate lineage for CDH1, in the ancestral Murinae lineage for both SDHC and MSH6 genes and the ancestral Muridae lineage for TSC1. Conclusion Identifying positive selection in the Primate, Hominidae, Muridae and Murinae lineages suggests an ancestral functional shift in these genes between the rodent and primate lineages. Analyses such as this, combining evolutionary theory and predictions - along with medically relevant data, can thus provide us with important clues for modeling human diseases

Boolean Dynamics with Random Couplings

This paper reviews a class of generic dissipative dynamical systems called N-K models. In these models, the dynamics of N elements, defined as Boolean variables, develop step by step, clocked by a discrete time variable. Each of the N Boolean elements at a given time is given a value which depends upon K elements in the previous time step. We review the work of many authors on the behavior of the models, looking particularly at the structure and lengths of their cycles, the sizes of their basins of attraction, and the flow of information through the systems. In the limit of infinite N, there is a phase transition between a chaotic and an ordered phase, with a critical phase in between. We argue that the behavior of this system depends significantly on the topology of the network connections. If the elements are placed upon a lattice with dimension d, the system shows correlations related to the standard percolation or directed percolation phase transition on such a lattice. On the other hand, a very different behavior is seen in the Kauffman net in which all spins are equally likely to be coupled to a given spin. In this situation, coupling loops are mostly suppressed, and the behavior of the system is much more like that of a mean field theory. We also describe possible applications of the models to, for example, genetic networks, cell differentiation, evolution, democracy in social systems and neural networks.Comment: 69 pages, 16 figures, Submitted to Springer Applied Mathematical Sciences Serie

Nightly treatment of primary insomnia with prolonged release melatonin for 6 months: a randomized placebo controlled trial on age and endogenous melatonin as predictors of efficacy and safety

<p>Background: Melatonin is extensively used in the USA in a non-regulated manner for sleep disorders. Prolonged release melatonin (PRM) is licensed in Europe and other countries for the short term treatment of primary insomnia in patients aged 55 years and over. However, a clear definition of the target patient population and well-controlled studies of long-term efficacy and safety are lacking. It is known that melatonin production declines with age. Some young insomnia patients also may have low melatonin levels. The study investigated whether older age or low melatonin excretion is a better predictor of response to PRM, whether the efficacy observed in short-term studies is sustained during continued treatment and the long term safety of such treatment.</p> <p>Methods: Adult outpatients (791, aged 18-80 years) with primary insomnia, were treated with placebo (2 weeks) and then randomized, double-blind to 3 weeks with PRM or placebo nightly. PRM patients continued whereas placebo completers were re-randomized 1:1 to PRM or placebo for 26 weeks with 2 weeks of single-blind placebo run-out. Main outcome measures were sleep latency derived from a sleep diary, Pittsburgh Sleep Quality Index (PSQI), Quality of Life (World Health Organzaton-5) Clinical Global Impression of Improvement (CGI-I) and adverse effects and vital signs recorded at each visit.</p> <p>Results: On the primary efficacy variable, sleep latency, the effects of PRM (3 weeks) in patients with low endogenous melatonin (6-sulphatoxymelatonin [6-SMT] ≤8 μg/night) regardless of age did not differ from the placebo, whereas PRM significantly reduced sleep latency compared to the placebo in elderly patients regardless of melatonin levels (-19.1 versus -1.7 min; P = 0.002). The effects on sleep latency and additional sleep and daytime parameters that improved with PRM were maintained or enhanced over the 6-month period with no signs of tolerance. Most adverse events were mild in severity with no clinically relevant differences between PRM and placebo for any safety outcome.</p> <p>Conclusions: The results demonstrate short- and long-term efficacy and safety of PRM in elderly insomnia patients. Low melatonin production regardless of age is not useful in predicting responses to melatonin therapy in insomnia. The age cut-off for response warrants further investigation.</p&gt

Genetic testing among high-risk individuals in families with hereditary nonpolyposis colorectal cancer

Hereditary nonpolyposis colorectal cancer (HNPCC) is frequently associated with constitutional mutations in a class of genes involved in DNA mismatch repair. We identified 32 kindreds, with germline mutations in one of three genes hMSH2, hMLH1 or hMSH6. In this study, we purposed to evaluate how many high-risk individuals in each family underwent genetic testing: moreover, we assessed how many mutation-positive unaffected individuals accepted colonoscopic surveillance and the main findings of the recommended follow-up. Families were identified through a population-based registry, or referred from other centres. Members of the families were invited for an education session with two members of the staff. When a kindred was consistent with HNPCC, neoplastic tissues were examined for microsatellite instability (MSI) and immunohistochemical expression of MSH2, MLH1 and MSH6 proteins. Moreover, constitutional mutations were searched by SSCP or direct sequencing of the whole genomic region. Of the 164 subjects assessed by genetic testing, 89 were gene carriers (66 affected - that is, with HNPCC-related cancer diagnosis - and 23 unaffected) and 75 tested negative. Among the 23 unaffected gene carriers, 18 (78.3%) underwent colonoscopy and four declined. On a total of 292 first degree at risk of cancer, 194 (66.4%) did not undergo genetic testing. The main reasons for this were: (a) difficulty to reach family members at risk, (b) lack of collaboration, (c) lack of interest in preventive medicine or 'fatalistic' attitude towards cancer occurrence. The number of colorectal lesions detected at endoscopy in gene carriers was significantly (P<0.01) higher than in controls (noncarriers). We conclude that a large fraction of high-risk individuals in mutation-positive HNPCC families does not undergo genetic testing, despite the benefits of molecular screening and endoscopic surveillance. This clearly indicates that there are still barriers to genetic testing in HNPCC, and that we are unable to provide adequate protection against cancer development in these families

The effects of low-impact mutations in digital organisms

<p>Abstract</p> <p>Background</p> <p>Avida is a computer program that performs evolution experiments with digital organisms. Previous work has used the program to study the evolutionary origin of complex features, namely logic operations, but has consistently used extremely large mutational fitness effects. The present study uses Avida to better understand the role of low-impact mutations in evolution.</p> <p>Results</p> <p>When mutational fitness effects were approximately 0.075 or less, no new logic operations evolved, and those that had previously evolved were lost. When fitness effects were approximately 0.2, only half of the operations evolved, reflecting a threshold for selection breakdown. In contrast, when Avida's default fitness effects were used, all operations routinely evolved to high frequencies and fitness increased by an average of 20 million in only 10,000 generations.</p> <p>Conclusions</p> <p>Avidian organisms evolve new logic operations only when mutations producing them are assigned high-impact fitness effects. Furthermore, purifying selection cannot protect operations with low-impact benefits from mutational deterioration. These results suggest that selection breaks down for low-impact mutations below a certain fitness effect, the <it>selection threshold</it>. Experiments using biologically relevant parameter settings show the tendency for increasing genetic load to lead to loss of biological functionality. An understanding of such genetic deterioration is relevant to human disease, and may be applicable to the control of pathogens by use of lethal mutagenesis.</p

Evolution favors protein mutational robustness in sufficiently large populations

BACKGROUND: An important question is whether evolution favors properties such as mutational robustness or evolvability that do not directly benefit any individual, but can influence the course of future evolution. Functionally similar proteins can differ substantially in their robustness to mutations and capacity to evolve new functions, but it has remained unclear whether any of these differences might be due to evolutionary selection for these properties. RESULTS: Here we use laboratory experiments to demonstrate that evolution favors protein mutational robustness if the evolving population is sufficiently large. We neutrally evolve cytochrome P450 proteins under identical selection pressures and mutation rates in populations of different sizes, and show that proteins from the larger and thus more polymorphic population tend towards higher mutational robustness. Proteins from the larger population also evolve greater stability, a biophysical property that is known to enhance both mutational robustness and evolvability. The excess mutational robustness and stability is well described by existing mathematical theories, and can be quantitatively related to the way that the proteins occupy their neutral network. CONCLUSIONS: Our work is the first experimental demonstration of the general tendency of evolution to favor mutational robustness and protein stability in highly polymorphic populations. We suggest that this phenomenon may contribute to the mutational robustness and evolvability of viruses and bacteria that exist in large populations