Synthesis and Biological Evaluation of Dideoxunucleosides Containing A Difluoromethylene Unit

Abstract

2′-difluoro and 3′-difluoro dideoxynucleosides containing thymine and cytosine as the base were synthesized. These compounds inhibited HeLa cell growth and Moloney leukemia virus to a modest degree.     

Towards pan-genome read alignment to improve variation calling

Background

Typical human genome differs from the reference genome at 4-5 million sites. This diversity is increasingly catalogued in repositories such as ExAC/gnomAD, consisting of >15,000 whole-genomes and >126,000 exome sequences from different individuals. Despite this enormous diversity, resequencing data workflows are still based on a single human reference genome. Identification and genotyping of genetic variants is typically carried out on short-read data aligned to a single reference, disregarding the underlying variation.

Results

We propose a new unified framework for variant calling with short-read data utilizing a representation of human genetic variation – a pan-genomic reference. We provide a modular pipeline that can be seamlessly incorporated into existing sequencing data analysis workflows. Our tool is open source and available online: https://gitlab.com/dvalenzu/PanVC.

Conclusions

Our experiments show that by replacing a standard human reference with a pan-genomic one we achieve an improvement in single-nucleotide variant calling accuracy and in short indel calling accuracy over the widely adopted Genome Analysis Toolkit (GATK) in difficult genomic regions.

     

Foraging conditions, tooth wear and herbivore body reserves: a study of female reindeer

Several aspects of the life history of reindeer (Rangifer tarandus) are related to the nutritional condition of the animals. Moreover, compensatory growth and fattening in summer decreases with age. The interaction of tooth wear and the standing crop of lichens on age-related variation in body size and tissue reserves was examined to evaluate the proximate causes of density-dependent food limitation on life history parameters in female reindeer. Studies in nine semi-domesticated free-ranging reindeer herds showed that molar height depended on the mean standing crop of terrestrial lichens in winter habitats. The extent of tooth wear had the strongest effect on body reserves among the oldest females (11–14 years). This indicates that severe tooth wear limits the animals′ ability to process food efficiently and, hence, to maintain their body reserves. Both tooth wear and the biomass of lichens influenced body mass in old females, probably because on heavily exploited winter ranges reindeer had to use higher proportions of lower-ranking coarser foods, especially dwarf shrubs. Received: 1 December 1997 / Accepted: 13 July 1998     

Offspring growth, survival and reproductive success in the bank vole: a litter size manipulation experiment

To estimate the optimality of brood size, it is essential to study the effects of brood size manipulation on offspring survival and reproductive success. Moreover, testing the generality of the hypothesis of reproductive costs requires experimental data from a diversity of organisms. Here I present data on the growth, survival and reproductive success of bank vole Clethrionomys glareolus individuals from manipulated litters. Furthermore, the survival of mothers whose litter size was manipulated was studied. At weaning, the mean weight of pups from enlarged litters was lower and from reduced litters higher compared to control litters. After winter, at the start of the breeding season, individuals from enlarged litters, especially males, were still lighter than individuals from the other two treatments. Litter enlargements did not increase the number of reproducing female offspring per mother, nor did the litter sizes of female offspring differ between treatments. There were no differences between treatments in winter survival of offspring after weaning, but among female offspring, weaning weight explained the survival probabilities over winter. A higher weight of females at winter determined the probability of starting to reproduce in spring. The survival of mothers did not seem to be influenced by litter manipulation performed the previous year. According to the results, mothers nursing enlarged or reduced litters do not gain any fitness benefits in terms of number of offspring surviving to breeding. The results are consistent with the majority of experiments conducted in birds, which have found costs of enlarged brood appearing as offspring trade-offs rather than parent trade-offs. Received: 14 December 1997 / Accepted: 1 March 1998     

Selection for population‐specific adaptation shaped patterns of variation in the photoperiod pathway genes in Arabidopsis lyrata during post‐glacial colonization

Spatially varying selection can lead to population‐specific adaptation, which is often recognized at the phenotypic level; however, the genetic evidence is weaker in many groups of organisms. In plants, environmental shifts that occur due to colonization of a novel environment may require adaptive changes in the timing of growth and flowering, which are often governed by location‐specific environmental cues such as day length. We studied locally varying selection in 19 flowering time loci in nine populations of the perennial herb Arabidopsis lyrata, which has a wide but patchy distribution in temperate and boreal regions of the northern hemisphere. The populations differ in their recent population demographic and colonization histories and current environmental conditions, especially in the growing season length. We searched for population‐specific molecular signatures of directional selection by comparing a set of candidate flowering time loci with a genomic reference set within each population using multiple approaches and contrasted the patterns of different populations. The candidate loci possessed approximately 20% of the diversity of the reference loci. On average the flowering time loci had more rare alleles (a smaller Tajima's D) and an excess of highly differentiated sites relative to the reference, suggesting positive selection. The strongest signal of selection was detected in photoperiodic pathway loci in the colonizing populations of Northwestern Europe, whereas no evidence of positive selection was detected in the Central European populations. These findings emphasized the population‐specific nature of selection and suggested that photoperiodic adaptation was important during postglacial colonization of the species.     

Juvenile Barn Swallows Hirundo rustica L. from late broods start autumn migration younger,fuel less effectively and show lower return rates than juveniles from early broods

Long‐distance migratory passerines may exhibit different post‐fledging rearing times between their early and late broods due to limited time and energy resources. This could affect the migratory fuelling behaviour, condition and fitness of juvenile birds. We analysed long‐term (13‐year) biometric data (body mass, fat score) on Barn Swallows ringed at the nest and later recaptured during their initial stages of autumn migration. The return rates of early‐ and late‐born juveniles after overwintering in Africa were further compared to estimate their fitness. We found that juveniles from late broods started migrating south on average 11 days younger compared with juveniles from early broods. Body masses of nestlings did not differ between early and late broods, but juveniles from late broods were in better condition after leaving the nest, possibly due to a longer period of parental care. Having started migration, juveniles from late broods were, however, less efficient in accumulating energy than juveniles from early broods. A younger departure age, together with less efficient fuelling of late brood juveniles, may partly explain the 39% lower return probability and hence lower fitness value of late‐brood juveniles. Our study is the first to show that juveniles from the early and late broods exhibit different fuelling behaviour and departure strategies (in terms of age and timing), which may be reflected in the fitness value of offspring.     

Invasion under a trade-off between density dependence and maximum growth rate

The invasion of alien species and genotypes is an increasing concern in contemporary ecology. A central question is, what life-history traits enable invasion amidst populations of wild species and conventional cultivars? In order to invade, the initially rare species must perform better than their resident competitors. We conducted a mathematical analysis and simulation of a two-species extension of the Maynard Smith and Slatkin model for population dynamics in discrete time to study the role of density dependence as different types of competition in the invasion of new species. The type of density dependence ranged from scramble to contest competition. This led to intrinsic dynamics of the species range from point equilibrium to cycles and chaos. The traits were treated either as free parameters or constrained by a trade-off resulting from a common fixed strength of density dependence or equilibrium density. Resident and intruder traits had up to ten-fold differences in all of the parameters investigated. Higher equilibrium density of the intruder allowed invasion. Under constrained equilibrium density, an intrinsically stable intruder could invade an unstable resident population. Scramble competition made a population more susceptible to invasion than contest competition (e.g., limitation by light or territory availability). This predicts that a population which is mainly limited by food (or nutrients in plants) is more likely to be invaded than a population limited by a hierarchical competition, such as light among plants. The intruder population may have an effect on the resident population's dynamics, which makes the traditional invasion analysis unable to predict invasion outcome.     

Molecular effects of lithium exposure during mouse and chick gastrulation and subsequent valve dysmorphogenesis

BACKGROUND: Lithium (Li) has been associated with cardiac teratogenicity in the developing fetus. We took advantage of the association of therapeutic administration of Li with an increase in heart defects to gain insight into both normal and pathological heart and valve development with GSK‐3 inhibition. The objective of this study was to define whether Li mimicry of canonical Wnt/β‐catenin signaling induces cardiac valve defects. METHODS: Li was administered by a single intraperitoneal injection to the pregnant mouse on embryonic day E6.75, much earlier than heretofore analyzed. On E15.5 developing heart defects were defined by Doppler ultrasound. The embryonic hearts were analyzed for changes in patterning of active canonical Wnt expression and nuclear factor of the activated T cells‐c1 (NFATc1), both key regulators of valve development. Li‐exposed chick embryos were used to define the early cell populations during gastrulation that are susceptible to GSK‐3 inhibition and may relate to valve formation. RESULTS: Li exposure during gastrulation decreased the number of prechordal plate (PP) cells that reached the anterior intestinal portal, a region associated with valve development. Li decreased expression of Hex, an endoderm cardiac inducing molecule, normally also expressed by the PP cells, and of Sox 4 at the anterior intestinal portal and NFAT, critical factors in valvulogenesis. CONCLUSIONS: Cells existing already during gastrulation are associated with valve formation days later. The Wnt/β‐catenin signaling in PP cells is normally repressed by Wnt antagonists and Hex is up‐regulated. The antagonism occurring at the receptor level is bypassed by Li exposure by its intracellular inactivation of GSK‐3 directly to augment Wnt signaling. Birth Defects Research (Part A), 2008. © 2008 Wiley‐Liss, Inc.     

Grazing tolerance of Gentianella amarella and other monocarpic herbs: why is tolerance highest at low damage levels?

Plants have adapted to compensate for the loss of vegetative biomass and reproductive potential caused by grazing. Shoot damage breaks down the correlative inhibition maintained by apical dominance. The consequent increased branching may lead to increased production of flowers and fruits in damaged plants, provided that enough resources, both in terms of meristems and nutrients, are available. In Gentianella amarella, the removal of the apex of the main stem (10% clipping) had no pronounced effect on branching and plant performance. In one of the two study populations, however, apically damaged plants produced more fruits than undamaged control plants. The plants also fully compensated for 50% removal of the main stem in terms of above-ground biomass, but their fruit production was reduced compared to control and apically damaged plants. After 75% clipping, fruit production was not significantly reduced compared to 50% clipping. Consequently, G. amarella showed highest tolerance in the presence of minor shoot damage. The pattern is qualitatively similar in some other monocarpic species (Gentianella campestris, Erysimum strictum and Rhinanthus minor). Multiple constraints as well as selective forces may shape these compensatory responses: (1) A lack of basal meristems may constrain tolerance of high damage levels. (2) Species with basal meristems may have a potential to tolerate major damage, but a shortage of resources or otherwise unfavourable growth conditions may constrain their compensatory ability. (3) It may be adaptive to have maximum tolerance of low and moderate damage levels if chemical defences reduce the risk of extensive shoot damage as well as the risk of repeated grazing. (4) The compensatory ability of monocarpic species may be affected by selective forces that favour fast vertical growth early in the season and unbranched architecture in undamaged conditions. Therefore, it is not the mere grazing history, but also other factors associated with growth conditions that are required to explain the variation in grazing tolerance.     

Use of sheep grazing in the restoration of semi‐natural meadows in northern Finland

Abstract. The biodiversity of species‐rich semi‐natural meadows is declining across Europe due to ceased management. In this study we aimed to find out how successfully the local species richness of an overgrown semi‐natural mesic meadow could be restored by sheep grazing after a long period of abandonment. The cover of vascular plant species in grazed plots and ungrazed exclosures was studied for five years and the responses of different functional plant groups were followed (herbs vs grasses, tall vs short species, species differing in flowering time, species representing different Grime's CSR strategies and species indicative of rich vs poor soil). Grazing increased species number by nearly 30%. On grazed plots the litter cover practically disappeared, favouring small herbs such as Rhinanthus minor, Ranunculus acris, Trifolium pratense and the grass Agrostis capillaris. Grazing decreased the cover of the late flowering tall herb Epilobium angustifolium but had no effect on the abundance of the early flowering tall herbs Anthriscus sylvestris or Geranium sylvaticum. We suggest that to succeed in restoration it is useful to determine the responses of different functional plant groups to grazing. Grassland managers need this information to optimize the methods and timing of management used in restoration. Additional management practices, such as mowing, may be needed in mesic meadows to decrease the dominance of tall species. The availability of propagules seemed to restrict further increase of species richness in our study area.