When epidemic cholera appeared in Haiti in October 2010, the medical community there had virtually no experience with the disease and needed rapid training as the epidemic spread throughout the country. We developed a set of training materials specific to Haiti and launched a cascading training effort. Through a training-of-trainers course in November 14-15, 2010, and department-level training conducted in French and Creole over the following 3 weeks, 521 persons were trained and equipped to further train staff at the institutions where they worked. After the training, the hospitalized cholera patients' case-fatality rate dropped from 4% to <2% by mid-December and was <1% by January 2011. Continuing in-service training, monitoring and evaluation, and integration of cholera management into regular clinical training will help sustain this success.
Research activities in the fine chemicals industry involve the generation and analysis of huge amounts of chemical and biological data, and this has led to the development of highly sophisticated, computer-based, chemical information systems to support the research [ 11. Most chemical databases contain two-dimensional structural data, i.e. planar chemical structure diagrams, but there is also increasing interest in the processing of three-dimensional structural data, e.g. from X-ray crystallography and molecular mechanics studies. In this paper, we summarize work in our laboratory over the last 3 years which seeks to determine the utility of parallel hardware for the efficient processing of the structural data that are contained in chemical information systems. Two of the very many different types of parallel computer [2] are discussed, these being the ICL Distributed Array Processor and the INMOS transputer.
Abstract Most aspects of the molecular biology of cells involve tightly coordinated intermolecular interactions requiring specific recognition at the nucleotide and/or amino-acid levels. This has led to long-standing interest in the degree to which constraints on interacting molecules result in conserved vs. accelerated rates of sequence evolution, with arguments commonly being made that molecular coevolution can proceed at rates exceeding the neutral expectation. Here, a fairly general model is introduced to evaluate the degree to which the rate of evolution at functionally interacting sites is influenced by effective population sizes ( N e ), mutation rates, strength of selection, and the magnitude of recombination between sites. This theory is of particular relevance to matters associated with interactions between organelle- and nuclear-encoded proteins, as the two genomic environments often exhibit dramatic differences in the power of mutation and drift. Although genes within low N e environments can drive the rate of evolution of partner genes experiencing higher N e , rates exceeding the neutral expectation require that the former also have an elevated mutation rate. Testable predictions, some counterintuitive, are presented on how patterns of coevolutionary rates should depend on the relative intensities of drift, selection, and mutation. Significance Statement A wide variety of features at the cellular level involve precise interactions between participating molecular partners, thereby requiring coordinated co-evolutionary changes within lineages. The same is true for ecological interactions between species. Although there has been much speculation on how such constraints might drive molecular evolutionary rates beyond the neutral expectation, there has been little formal evolutionary theory to evaluate the generality of such claims. Here, a general framework is developed for ascertaining how rates of sequence evolution depend on the population-genetic environments of both interacting partner molecules. Although the features of one site can indeed drive the evolution of the other, only under restrictive conditions does this process push rates beyond the neutral expectation.
A suite of computer programs has been devised to generate articulated subject indexes with machine assistance. The suite has been written for the ICL 1900 series of machines in PLAN assembly language. The application of the index generation algorithm necessitates a double sorting operation. The first of these is straightforward. The strategy of the second is determined by the nature of the algorithm for rearranging index phrases, which is context-sensitive, and therefore requires special procedures for organising the data in core storage. The programs incorporate both tree and letter-table systems for dictionary look-up, and use simple list processing techniques.
Phagocytosis, the ingestion of cells by other cells, is ubiquitous among eukaryotic life. It is required for food uptake in many single-celled species and for the immune response in multicellular species. The origin of phagocytosis and its role in the evolution of endomembranes and the eukaryotic cell remains obscure. Drawing on a wealth of empirical data, we integrate prey capture, engulfment, and internal and external digestion into a mathematical evolutionary model that quantifies the fitness of a primitive phagocytoser relative to a non-phagocytosing ancestor. We reveal the conditions under which a non-phagocytosing predator that digests its prey externally can persist. We also show that the phagocytoser can outperform the ancestor in a broad range of situations, despite the cost associated with producing a phagocytic cup. Parameter variations delineate how fast engulfment needs to be for phagocytosis to be advantageous, providing clear benchmarks for interpreting the importance of results in genetic knockout studies and mechanical models. The phagocytoser still outperforms the ancestor when food vacuoles can't fuse back to the plasma membrane, providing arguments in favor of the gradual evolution of phagocytosis and for phagocytosis as the initiator of the endomembrane system.
Errors can occur at any level during the replication and transcription of genetic information. Genetic mutations derived mainly from replication errors have been extensively studied. However, fundamental details of transcript errors, such as their rate, molecular spectrum, and functional effects, remain largely unknown. To globally identify transcript errors, we applied an adapted rolling-circle sequencing approach to Escherichia coli, Bacillus subtilis, Agrobacterium tumefaciens, and Mesoplasma florum, revealing transcript-error rates 3 to 4 orders of magnitude higher than the corresponding genetic mutation rates. The majority of detected errors would result in amino-acid changes, if translated. With errors identified from 9929 loci, the molecular spectrum and distribution of errors were uncovered in great detail. A G→A substitution bias was observed in M. florum, which apparently has an error-prone RNA polymerase. Surprisingly, an increased frequency of nonsense errors towards the 3′ end of mRNAs was observed, suggesting a Nonsense-Mediated Decay-like quality-control mechanism in prokaryotes.
Abstract Nonadditive genetic variation and genetic disequilibrium are two important factors that influence the evolutionary trajectory of natural populations. We assayed quantitative genetic variation in a temporary-pond-dwelling population of Daphnia pulex over a full season to examine the role of nonadditive genetic variation and genetic disequilibrium in determining the short-term evolutionary trajectory of a cyclic parthenogen. Quantitative traits were influenced by three factors: (1) clonal selection significantly changed the population mean phenotype during the course of the growing season; (2) sexual reproduction and recombination led to significant changes in life-history trait means and the levels of expressed genetic variation, implying the presence of substantial nonadditive genetic variation and genetic disequilibrium; and (3) Egg-bank effects were found to be an important component of the realized year-to-year change. Additionally, we examined the impact of genetic disequilibria induced by clonal selection on the genetic (co)variance structure with a common principal components model. Clonal selection caused significant changes in the (co)variance structure that were eliminated by a single bout of random mating, suggesting that a build-up of disequilibria was the primary source of changes in the (co)variance structure. The results of this study highlight the complexity of natural selection operating on populations that undergo alternating phases of sexual and asexual reproduction. Corresponding Editor: D. Waller
One of the great unsolved mysteries of evolutionary biology concerns the genetic mechanisms underlying the origin of genomic incompatibilities between species. Two prevailing thoughts are that such incompatibilities often result from epistatically interacting genes that act as loss-of-function alleles in hybrid backgrounds or from chromosomal rearrangements that result in mis-segregation during meiosis in hybrids. However, it is unclear how genes that cause a radical breakdown in hybrids arise without reducing fitness within species, and numerous cases of speciation appear to be unassociated with obvious chromosomal rearrangements. Here we suggest that duplicate genes, and more generally any kind of genomic redundancies, provide a powerful substrate for the origin of genomic incompatibilities in isolated populations. The divergent resolution of genomic redundancies, such that one population loses function from one copy while the second population loses function from a second copy at a different chromosomal location, leads to chromosomal repatterning such that gametes produced by hybrid individuals can be completely lacking in functional genes for a duplicate pair. Under this model, incompatibility factors accumulate with essentially no loss of fitness within populations as postulated under the Bateson-Dobzhansky-Muller (BDM) model of speciation and despite the fact that they arise from degenerative mutations. However, unlike the situation often envisioned under the BDM model, no change in the mode of gene action in hybrid backgrounds need be invoked. The plausibility of this model derives from a number of recent observations, including the fact that most genomes harbor substantial numbers of gene duplicates whose turnover is common and ongoing process and the fact that many genes have complex regulatory regions that facilitate their divergent resolution in sister taxa.
Mutations in the mitochondrial genome have been implicated in numerous human genetic disorders and offer important data for phylogenetic, forensic, and population genetic studies. Using a long-term series of Caenorhabditis elegans mutation accumulation lines, we performed a wide-scale screen for mutations in the mitochondrial genome that revealed a mutation rate that is two orders of magnitude higher than previous indirect estimates, a highly biased mutational spectrum, multiple mutations affecting coding function, as well as mutational hotspots at homopolymeric nucleotide stretches.
