The two-electron gate in photosynthetic bacteria

This paper gives a historical and personal account of the author's work in Rod Clayton's laboratory, when he observed the first evidence of the two-electron gate in bacterial reaction center. Colin Wraight had independently discovered this phenomenon at the same time. The high similarity between the acceptor side of Photosystem II (PS II) and of bacterial reaction centers was one of the first proofs for a profound homology between these two photosystems. This revised version was published online in June 2006 with corrections to the Cover Date.     

Web-based genome-wide association study identifies two novel loci and a substantial genetic component for Parkinson's disease

Although the causes of Parkinson's disease (PD) are thought to be primarily environmental, recent studies suggest that a number of genes influence susceptibility. Using targeted case recruitment and online survey instruments, we conducted the largest case-control genome-wide association study (GWAS) of PD based on a single collection of individuals to date (3,426 cases and 29,624 controls). We discovered two novel, genome-wide significant associations with PD-rs6812193 near SCARB2 (p = 7.6 × 10(-10), OR = 0.84) and rs11868035 near SREBF1/RAI1 (p = 5.6 × 10(-8), OR = 0.85)-both replicated in an independent cohort. We also replicated 20 previously discovered genetic associations (including LRRK2, GBA, SNCA, MAPT, GAK, and the HLA region), providing support for our novel study design. Relying on a recently proposed method based on genome-wide sharing estimates between distantly related individuals, we estimated the heritability of PD to be at least 0.27. Finally, using sparse regression techniques, we constructed predictive models that account for 6%-7% of the total variance in liability and that suggest the presence of true associations just beyond genome-wide significance, as confirmed through both internal and external cross-validation. These results indicate a substantial, but by no means total, contribution of genetics underlying susceptibility to both early-onset and late-onset PD, suggesting that, despite the novel associations discovered here and elsewhere, the majority of the genetic component for Parkinson's disease remains to be discovered.     

Evolution of the structure and composition of house mouse satellite DNA sequences in the subgenus Mus (Rodentia: Muridea): a cytogenomic approach

The composition and orientation of the house mouse satellite DNA sequences (minor, major, TLC) were investigated by a FISH and CO-FISH approach in 11 taxa belonging to three clades of the subgenus Mus. Using a phylogenetic framework, our results highlighted two distribution patterns. The TLC satellite, the most recently discovered satellite, was present in all clades but varied quantitatively among species. This distribution supported its appearance in the ancestor of the subgenus followed by independent evolution in species of each clade. In contrast, the minor and major satellites occurred in only two clades of the subgenus indicating the simultaneous and recent amplification of these sequences. In addition, although qualitative differences in the composition and orientation of the satellite sequences were observed among the taxa, none of the features studied were unique to the house mouse and could account for the extensive chromosomal plasticity evidenced in Mus musculus domesticus.     

Accounting for Population Structure in Gene-by-Environment Interactions in Genome-Wide Association Studies Using Mixed Models

Although genome-wide association studies (GWASs) have discovered numerous novel genetic variants associated with many complex traits and diseases, those genetic variants typically explain only a small fraction of phenotypic variance. Factors that account for phenotypic variance include environmental factors and gene-by-environment interactions (GEIs). Recently, several studies have conducted genome-wide gene-by-environment association analyses and demonstrated important roles of GEIs in complex traits. One of the main challenges in these association studies is to control effects of population structure that may cause spurious associations. Many studies have analyzed how population structure influences statistics of genetic variants and developed several statistical approaches to correct for population structure. However, the impact of population structure on GEI statistics in GWASs has not been extensively studied and nor have there been methods designed to correct for population structure on GEI statistics. In this paper, we show both analytically and empirically that population structure may cause spurious GEIs and use both simulation and two GWAS datasets to support our finding. We propose a statistical approach based on mixed models to account for population structure on GEI statistics. We find that our approach effectively controls population structure on statistics for GEIs as well as for genetic variants.     

Cellular regulation by protein phosphorylation

A historical account of the discovery of reversible protein phosphorylation is presented. This process was uncovered in the mid 1950s in a study undertaken with Edwin G. Krebs to elucidate the complex hormonal regulation of skeletal muscle glycogen phosphorylase. Contrary to the known activation of this enzyme by AMP which serves as an allosteric effector, its hormonal regulation results from a phosphorylation of the protein by phosphorylase kinase following the activation of the latter by Ca²⁺ and ATP. The study led to the establishment of the first hormonal cascade of successive enzymatic reactions, kinases acting on kinases, initiated by cAMP discovered by Earl Sutherland. It also showed how two different physiological processes, carbohydrate metabolism and muscle contraction, could be regulated in concert.     

Five mutations in N-terminus confer thermostability on mesophilic xylanase

The termini of a pair of xylanases, one of mesophilic and one of thermophilic origin, was studied by molecular dissection and systematic mutagenesis. The thermostability of the mesophilic xylanase SoxB from Streptomyces olivaceovirdis was significantly improved by substituting its 33 N-terminal amino acid residues with the corresponding residues of the thermophilic xylanase TfxA from Thermomonospora fusca. Five amino acid substitutions, which clustered in one of the regions of the N-terminus, were discovered, for the first time, to account for the majority of the improvement in thermostability of SoxB. Further systematic mutagenesis and analysis of the five mutations demonstrated that comprehensive synergism of the five mutations was involved in conferring the thermostability on the SoxB. Moreover, when the five thermostabilizing mutations were introduced into two other G/11 xylanases, SlxB from Streptomyces lividans and AnxB from Aspergillus niger, their thermostabilities were also dramatically enhanced.     

Differences in the relative resistance of two carrot cultivars to carrot fly attack over five seasons

A comparison was made over five seasons of carrot fly (Psila rosae) damage on two carrot cultivars, Sytan and Danvers, which represented the extremes of resistance discovered in screening trials at Wellesbourne. Plants were harvested regularly during the seasons and at each harvest the number and weight of roots was recorded and carrot fly damage was assessed using various techniques; in 1979-80 the numbers of carrot fly larvae and pupae in and around root samples were counted. The experiments confirmed repeatedly the relative resistance of cv. Sytan compared with Danvers. The estimated reduction in carrot fly larvae on Sytan relative to Danvers in early November in four seasons ranged from 40% to 67%. When tested against first generation carrot fly attack the reduction in larvae on Sytan was 54%. There were 45% fewer mines per root on Sytan resulting in less damage at each harvest in all seasons. Larvae took longer to develop on Sytan than Danvers and 18% more plants of Sytan survived carrot fly attack. Differences in seedstock, season, sowing time, generation of carrot fly, plant size and density did not account for observed differences in damage between the two cultivars. The studies indicated satisfactory practical techniques for assessing carrot fly damage in cultivar screening trials.     

Evidence for low‐level hybridization between two allochronic populations of the pine processionary moth,Thaumetopoea pityocampa (Lepidoptera: Notodontidae)

Divergence between populations sharing the same habitat can be initiated by different reproductive times, leading to allochronic differentiation. A spatially localized allochronic summer population (SP) of the pine processionary moth Thaumetopoea pityocampa, recently discovered in Portugal, occurs in sympatry with the local winter population (WP). We examined the level of genetic differentiation between the two populations and estimated the current gene flow within the spatial framework of their co‐occurrence. Mitochondrial data indicated that the two sympatric populations were genetically closer than other WP populations. Conversely, microsatellite genotyping uncovered greater differentiation between the two sympatric populations than between allopatric ones. While male trapping confirmed that reproduction of SP and WP occurred at distinct times, clustering approaches demonstrated the presence of a few LateSP individuals emerging within the WP flight period, although genetically identified as SP. We also identified rare recent hybridization events apparently occurring mainly in the margins of the current SP range. The ongoing gene flow detected between the ancestral and the emerging allochronic populations revealed an incomplete reproductive isolation, which must therefore be taken into account and integrated with studies focussed on ecological drivers, so that a complete understanding of the ongoing speciation process might be achieved.     

Novel PDGF family members: PDGF-C and PDGF-D

Platelet-derived growth factors (PDGFs) were discovered almost two decades ago. The classical PDGF polypeptide chains, PDGF-A and PDGF-B, are well studied and they regulate a number of physiological and pathophysiological processes in many types of mesenchymal cells via two receptor tyrosine kinases, PDGF receptors alpha and beta. Recently, two additional PDGF polypeptide chains were discovered, namely PDGF-C and PDGF-D. The discovery of two additional ligands for the two PDGF receptors suggests that PDGF-mediated signaling is more complex than previously anticipated.     

Experiments in a Monastery Garden

SYNOPSIS. After a brief account of my early education, studyat the University of Wien, and preliminary experiments on hybridizationconducted at the Augustinian Monastery in Brünn, Austria,I state the reasons for selecting certain features of the ediblepea, Pisum sativum, for extensive investigation of their inheritance.After eight years I reported my results to the Brünn Societyfor the Study of Natural Science, and they were published inthe following year (1866) in the Proceedings of the Society.I discovered two basic principles of inheritance: the law ofsegregation and the law of independent assortment of hypotheticalunits of heredity that I called Elemente. I conclude with someremarks on the possible relation of my work to the evolutionof organic form and on my disappointment that my studies donot seem to be known or understood, and that because of my administrativeduties at themonastery, now being the Abbot, I have no timefor further investigations.     

Bootstrapping of gene-expression data improves and controls the false discovery rate of differentially expressed genes

The ordinary-, penalized-, and bootstrap t-test, least squares and best linear unbiased prediction were compared for their false discovery rates (FDR), i.e. the fraction of falsely discovered genes, which was empirically estimated in a duplicate of the data set. The bootstrap-t-test yielded up to 80% lower FDRs than the alternative statistics, and its FDR was always as good as or better than any of the alternatives. Generally, the predicted FDR from the bootstrapped P-values agreed well with their empirical estimates, except when the number of mRNA samples is smaller than 16. In a cancer data set, the bootstrap-t-test discovered 200 differentially regulated genes at a FDR of 2.6%, and in a knock-out gene expression experiment 10 genes were discovered at a FDR of 3.2%. It is argued that, in the case of microarray data, control of the FDR takes sufficient account of the multiple testing, whilst being less stringent than Bonferoni-type multiple testing corrections. Extensions of the bootstrap simulations to more complicated test-statistics are discussed.     

DrugBank screening revealed alitretinoin and bexarotene as liver X receptor modulators

In silico screening of DrugBank database to detect liver X receptor (LXR) agonism of marketed drugs using a self-organizing map and successive LXR-Gal4 hybrid reporter gene assay evaluation in vitro discovered alitretinoin and bexarotene as partial liver X receptor agonists. Dose-response curves demonstrated that plasma concentrations observed in clinical trials are sufficient for LXR activation and thus could account for LXR-mediated side-effects such as hypercholesterolemia and hyperlipidemia. The discovered drugs are the first reported dual LXR/RXR agonists and can serve as lead structures for LXR and dual LXR/RXR modulator development.     

Interaction of erythrocytes with human serum proteins. I. Analysis of the effect of pH and ionic strength of the medium.

The effect of ionic parameters of the medium (pH and ionic strength) on the processes of interaction of tannin-treated erythrocytes and the protein fractions of human serum (macroglobulins, microbulins and albumin) was studied in factorial experiments. Complex effect of these parametres on the processes under investigation and optimum conditions of erythrocyte sensitization were established. Subsequent fixation of antibodies by the erythrocyte diagnostic and their agglutinating activity are manifested in different mannera depending on the conditions of preceding sensitization. Important peculairities were discovered in the mechanism of interaction between the erythrocytes and various serum proteins. The obtained results should be taken into account in the production of erythrocyte antigen and antibody diagnosticums.     

Cellular arrangements and surface topography during early development in embryos of Ilyanassa obsoleta

Summary

Surface architecture and selected ultrastructural features of normal embryos of the marine gastropod Ilyanassa obsoleta have been investigated using scanning and transmission electron microscopy. A re-examination of the classic account of Anthony Clement on temporal and division patterns in normal and lobeless embryos confirms most of his observations; a few differences, involving the size and positioning of micromere 4d and its derivatives, are noted. Several hypotheses are presented to account for zonular distribution of longer microvilli on some blastomere surfaces and progressive diminution of microvilli on micromere surfaces, especially the leading edge micromeres (LEMs), during postulated epibolic spreading movements. Microfilaments, discovered in the cortical regions of the LEMs, are described, and a role for these structures in gastrulation is proposed.     

Allopatric origin of cryptic butterfly species that were discovered feeding on distinct host plants in sympatry

Surveys of tropical insects are increasingly uncovering cryptic species – morphologically similar yet reproductively isolated taxa once thought to comprise a single interbreeding entity. The vast majority of such species are described from a single location. This leaves us with little information on geographic range and intraspecific variation and limits our ability to infer the forces responsible for generating such diversity. For example, in herbivorous and parasitic insects, multiple specialists are often discovered within what were thought to be single more generalized species. Host shifts are likely to have contributed to speciation in these cases. But when and where did those shifts occur, and were they facilitated by geographic isolation? We attempted to answer these questions for two cryptic species within the butterfly Cymothoe egesta that were recently discovered on different host plants in central Cameroon. We first used mtDNA markers to separate individuals collected on the two hosts within Cameroon and then extended our analysis to incorporate individuals collected across the entire pan‐Afrotropical range of the original taxon. To our surprise, we found that the species are almost entirely allopatric, dividing the original range and overlapping only in the narrow zone of West‐Central Africa where they were first discovered in sympatry. This finding, combined with analyses of genetic variation within each butterfly species, strongly suggests that speciation occurred in allopatry, probably during the Pleistocene. We discuss the implications of our results for understanding speciation among other cryptic species recently discovered in the tropics and argue that more work is needed on geographic patterns and host usage in such taxa.     

青海发现极北朱顶雀和白腰朱顶雀

<正>2013年9月,在青海省大通县庙沟乡落叶松林内(36°54′N,101°38′E,海拔2 702 m)观察到一群额红色,嘴黄色短尖,翅羽尽黑,胸部粉红色,腰几乎为白色的雀形目鸟类。经鉴定为极北朱顶雀(Carduelis hornemanni)。2014年3月,在青海省海东市平安县沙沟人工小型林场(36°20′N,102°02′E,海拔2 980 m)观察到十几只头顶红色,眉纹黄白色,嘴短尖,胸腹部多黄白相间纵纹,翅上有白色横斑的雀形目鸟类。经鉴定为白腰朱顶     

The receptor concept: a continuing evolution

This review briefly summarizes the development of the receptor concept, the identification of receptors based first on biological response data and subsequently on radioligand binding properties, and the biological and physiological understandings that these approaches have made possible. The development of receptor characterization began with receptors that ultimately were discovered to mediate response by coupling to G-binding proteins, also known as G protein-coupled receptors (GPCRs). Consequently, many if not all of the examples in this overview will describe studies characterizing GPCRs in general, and adrenergic receptors in particular. The purpose of this review, however, is not a detailed chronological account of a huge literature, but rather an overview of the fundamental questions posed and answered by these studies.     

Effect of an anomalous broadening of the synchronization band after electric stimulation of heart tissues

Synchronization effects of the second order induced by a change of the action potential (AP) shape in relation to the frequency of periodic stimulation were studied. Mechanism of anomalous increase of the synchronization band at periodic stimulation of the heart fibers was explained. By means of a modified method of synchronization diagrams the synchronization bands were calculated for possible stimulation regimes taking into account a change in RP shape and dynamic threshold (DT) depending on the frequency of the initiated regimes. Regions of stimulating signals parameters (multiplicity regions or prolonging regions) were discovered, within the range of which the same stimulating signal may induce different synchronization regimes. Physiological meaning of the existence of anomalous synchronization regimes which significantly broaden the adaptation possibilities of the heart is discussed.