Mining the pharmacogenomics literature--a survey of the state of the art

This article surveys efforts on text mining of the pharmacogenomics literature, mainly from the period 2008 to 2011. Pharmacogenomics (or pharmacogenetics) is the field that studies how human genetic variation impacts drug response. Therefore, publications span the intersection of research in genotypes, phenotypes and pharmacology, a topic that has increasingly become a focus of active research in recent years. This survey covers efforts dealing with the automatic recognition of relevant named entities (e.g. genes, gene variants and proteins, diseases and other pathological phenomena, drugs and other chemicals relevant for medical treatment), as well as various forms of relations between them. A wide range of text genres is considered, such as scientific publications (abstracts, as well as full texts), patent texts and clinical narratives. We also discuss infrastructure and resources needed for advanced text analytics, e.g. document corpora annotated with corresponding semantic metadata (gold standards and training data), biomedical terminologies and ontologies providing domain-specific background knowledge at different levels of formality and specificity, software architectures for building complex and scalable text analytics pipelines and Web services grounded to them, as well as comprehensive ways to disseminate and interact with the typically huge amounts of semiformal knowledge structures extracted by text mining tools. Finally, we consider some of the novel applications that have already been developed in the field of pharmacogenomic text mining and point out perspectives for future research.     

Theoretical study of the optimal shape of the front profile of the lens in the eye of the scallop,Pecten

The optimal shape of the front profile of the thick lens in the eye of the scallop,Pecten is theoretically, geometric optically investigated as a function of the refractive index of the lens and the retina, as well as of the geometrical parameters of the eye. The shape of the theoretical front surfaces is compared with that of the real, experimentally determined front face of the lens. The degree of correction of the lens for spherical aberration of the reflecting spherical mirror in thePecten eye is examined. The optimal shape of the front profile of the lens depends strongly on a set of parameters, such that a certain fine tuning is required among them to assure a full correction for spherical aberration. The extreme variability of the eye parameters and the shape of the front face of the lens in the scallop is inconsistent with this fine tuning requirement. The degree of correction of thePecten lens for spherical aberration might not be as good as it could be, a possible biooptical reason for which is discussed.     

Editorial: Defining the membrane precursor supporting the nucleation of the phagophore

How does the phagophore form? Which membrane acts as a platform for its biogenesis? Over the years, extensive use of microscopy techniques have led to the controversial identification of multiple potential membranes as precursors for phagophore nucleation and/or for the supply of lipids to the expanding compartment. Nevertheless, none of these studies has established a direct functional link between membrane sources and autophagosome biogenesis. Addressing this point, in a recent study highlighted by a punctum in this issue, Ge and coworkers developed an in vitro approach to determine the identity of the membranes responsible for the lipidation of LC3, thus identifying the ER-Golgi intermediate compartment (ERGIC) as a potential key determinant of phagophore biogenesis.     

Distribution and properties of the genes encoding the biosynthesis of the bacterial cofactor, pyrroloquinoline quinone

Pyrroloquinoline quinone (PQQ) is a small, redox active molecule that serves as a cofactor for several bacterial dehydrogenases, introducing pathways for carbon utilization that confer a growth advantage. Early studies had implicated a ribosomally translated peptide as the substrate for PQQ production. This study presents a sequence- and structure-based analysis of the components of the pqq operon. We find the necessary components for PQQ production are present in 126 prokaryotes, most of which are Gram-negative and a number of which are pathogens. A total of five gene products, PqqA, PqqB, PqqC, PqqD, and PqqE, are identified as being obligatory for PQQ production. Three of the gene products in the pqq operon, PqqB, PqqC, and PqqE, are members of large protein superfamilies. By combining evolutionary conservation patterns with information from three-dimensional structures, we are able to differentiate the gene products involved in PQQ biosynthesis from those with divergent functions. The observed persistence of a conserved gene order within analyzed operons strongly suggests a role for protein-protein interactions in the course of cofactor biosynthesis. These studies propose previously unidentified roles for several of the gene products, as well as identifying possible new targets for antibiotic design and application.     

Forming of the visual cognitive structures in the monkey conditioned-reflex behaviour: the dependence on the sensory information

In monkeys, changes in size and shape of figures led to a significant decrease of correct solutions in training and a considerable increase of refusals from solution of tasks as well as the time of their motor response. The invariance of differentiation in this case was achieved after additional training. The data obtained show that, based on the stimulus sensory processing in conditioned-reflex training, in the long-term memory some differentiating signs are formed: the cognitive structures (the functional neurophysiological mechanisms) maintaining the classification of visual images. With these structures, temporary conditioned connection will be established. Their formation will be determined by the type of sensory information and provided for by existence in the long-term memory of separate subsystems for spatial as well as non-spatial information.     

Evidence that the voltage-dependent component in the fertilization process is contributed by the sperm

To investigate the mechanisms that account for the voltage dependence of fertilization and provide an electrical block to polyspermy, we studied cross-fertilizations between three species of amphibians having different degrees of voltage dependence. Anurans, such as the toad Bufo japonicus, as well as the primitive urodele Hynobius nebulosus, have voltage-dependent fertilization; other urodeles, such as Cynops pyrrhogaster, have voltage-independent fertilization (Y. Iwao, 1989, Dev. Biol. 134, 438-445). Entry of Hynobius sperm into Cynops eggs was blocked by clamping the egg's membrane potential at +40 mV, as is the case for fertilization of Hynobius eggs with Hynobius sperm, but not for fertilization of Cynops eggs with Cynops sperm. Therefore, fertilization was voltage dependent in an experimental condition where only the sperm could be contributing this characteristic. The voltage-dependent properties of fertilization between Bufo eggs and Hynobius sperm were also characteristic of the sperm species; fertilization was blocked at +50 mV as in Hynobius fertilization, but not at +20 mV as in Bufo fertilization. These results support the conclusion that the voltage dependence of fertilization results from a component contributed by the sperm.     

Septins: the fourth component of the cytoskeleton

Septins belong to a family of proteins that is highly conserved in eukaryotes and is increasingly recognized as a novel component of the cytoskeleton. All septins are GTP-binding proteins that form hetero-oligomeric complexes and higher-order structures, including filaments and rings. Recent studies have provided structural information about the different levels of septin organization; however, the crucial structural determinants and factors responsible for septin assembly remain unclear. Investigations on the molecular functions of septins have highlighted their roles as scaffolds for protein recruitment and as diffusion barriers for subcellular compartmentalization in numerous biological processes, including cell division and host-microorganism interactions.     

Youth and personality formation--the world belongs to the strength of the young and to the wisdom of the elderly (a point of view of the communicologist)

It is known from the pedagogic, didactic and experience coordinates that a man doesn't become better by using words but by his actions. They are matchless examples for the self-apprehension process and the perception of the action itself as well as the only worthy and accurate offer for the assessment of the range and the significance of the achieved result. From the earliest stage of their life, from the childhood and then later on in different stages of their development and growth, the human being as a social being has a double need: to feel himself in the range of his "I" and to feel himself as a member of a group, a family and of the society in general. Satisfying the sense and the level of those needs doubtlessly depends on the examples given by the life itself and the circumstances of the living within the family, the school and finally the society, that is, the surroundings where the individual is affirming himself by his individual creative capability and skills with which he realizes himself as a subject on its own as well as within the social group he lives and works in. The conditions of the life and work of the elderly are necessary for this important and precious task in the development of a young man so that the applications of their experiences could ensure reliable guidelines for the harmony and success of the life and work of the young. On this bridge of generations the experience of the old is affirmed along with the need for its aimed, creative and fruitful offer to the young in the dynamic process of their development to the maturity and creativity.     

Epithelial carcinogenesis in the mouse: correlating the genetics and the biology.

Tumour formation relies on a complex combination of genetic and environmental factors. In particular, the contributions from inherited predisposition genes as well as carcinogens, for example from cigarettes or in the diet, are amongst the major contributors to tumorigenesis. Since the study of such processes in particularly difficult in human cancers, the availability of a well-defined model system is of obvious benefit. The mouse skin model of multistage carcinogenesis offers an excellent tool for the study of the target cells, the target genes and the biological events associated with neoplasia. In this system, tumorigenesis occurs in a series of defined stages, each of which is characterized by specific and reproducible alterations in genes such as H-ras, cyclin D1, p53 and p16INK4A. Additional changes occur in the production of, or response to, factors such as transforming growth factor beta (TGF beta). These genetic and biological alterations are mirrored in human tumours of epithelial origin. Hence, research into the general principles of tumour initiation, promotion and progression in the context of the mouse skin model is likely to prove valuable in the continual search for new methods for the diagnosis, prevention, and therapeutic treatment of human cancers.     

Infrastructure and the environment in the Anthropocene

For centuries, man‐made infrastructure has been viewed as separate from natural systems. Yet in the past few centuries, as the scale and scope of human activities have dramatically increased, there is accumulating evidence that natural systems are becoming increasingly, and in some cases entirely, managed by humans. The dichotomy between infrastructure and the environment is narrowing, and natural systems are increasingly becoming human design spaces. This is already apparent with the management of hydrologic systems for urban water supply, wildlife, agriculture, forests, and even the atmosphere, and we can expect management of the environment to become more so as human activities grow. Yet our infrastructure largely remains obdurate. They are designed to last for long times even as changes in the environment and technology accelerate. As such, our current infrastructure paradigms fail at the level of the complex, integrated systems and behaviors that characterize the Anthropogenic Earth. Infrastructure in the future will need to be designed for adaptive capacity and the complexities associated with techno‐environmental systems.     

Shaping the T-cell repertoire in the periphery

Selection of T cells does not end with events in the thymus, but continues in extrathymic tissues and for the life of the organism. In this review, we examine how self-reactive T cells are rendered harmless and the processes that select for T cells that are most efficient at combating pathogens. The implications of peripheral T-cell selection for the immune response as animals age are discussed as is the critical role of dendritic cells in directing T-cell differentiation.     

Animal experiments using mammals are essential to the study on the mechanisms of phenomena produced in the human body in the space environment.

The animal experiments have contributed to the physiology and medicine concerned with the care and cure of patients as well as with an understanding of mechanisms of various diseases and human health. In particular, the numerous mammals have been used for the medical researches. Similarly, to investigate the phenomena in the human body that occur in the space environment, the various mammals have been used for the medical researches in space. Since the human with frontier spirits will never stop continuing the space development and utilization, the space medical and physiological researches using mammals as well as subjects are more important and necessary for the future space activities. The mammal modules in spacecrafts and space station are produced for the rodents at this time. Therefore, from various viewpoints, the rats and mice are the first choice for space mammal experiments of medical or life science researches and space modules for the mammal should be carefully and extensively designed.     

The beta-subunit of the protein-conducting channel of the endoplasmic reticulum functions as the guanine nucleotide exchange factor for the beta-subunit of the signal recognition particle receptor

Cotranslational protein transport to the endoplasmic reticulum is controlled by the concerted interaction of three GTPases: the SRP54 subunit of the signal recognition particle (SRP) and the alpha- and beta-subunits of the SRP receptor (SR). SRbeta is related to ADP-ribosylation factor (ARF)-type GTPases, and the recently published crystal structure of SRbeta-GTP in complex with the binding domain of SRalpha suggested that SRbeta, like all ARF-type GT-Pases, requires a guanine nucleotide exchange factor (GEF) for function. Searching the sequence data base, we identified significant sequence similarity between the Sec7 domain of ARF-GEFs and the cytosolic domains of the beta-subunits of the two homologous heterotrimeric protein-conducting channels in yeast. Using a fluorescence nucleotide exchange assay, we show that the beta-subunits of the heterotrimeric protein-conducting channels function as the GEFs for SRbeta. Both the cytosolic domain of Sec61beta as well as the holo-Sec61beta, when part of the isolated trimeric Sec61p complex, function as the GEF for SRbeta, whereas the same Sec61beta, when part of the heptameric complex that facilitates posttranslational protein transport, is inactive as the GEF for SRbeta     

Effect of prolactin and androgen on the expression of the female-attracting pheromone silefrin in the abdominal gland of the newt, Cynops ensicauda

Silefrin is a sodefrin-like, female-attracting pheromone comprising 10 amino acids that was isolated from the abdominal gland of the sword-tailed newt, Cynops ensicauda. Hormonal effects on the silefrin precursor mRNA expression and silefrin content in the abdominal gland were investigated in the present study by using Northern blot analysis and radioimmunoassay, respectively. In the abdominal gland of newts treated with prolactin (PRL) plus testosterone propionate (TP), silefrin precursor mRNA expression was markedly enhanced as compared with that in the newts injected with saline, PRL, or TP. Values for radioimmunoassayable silefrin content in the abdominal gland paralleled those for the silefrin precursor mRNA levels. Moreover, silefrin precursor mRNA signals, as revealed by in situ hybridization, as well as stainability of immunoreactive silefrin were much more intense in the epithelial cells of the abdominal gland of the PRL-plus-TP-treated animals than in those of controls. We thus conclude that PRL and androgen are important factors for enhancing silefrin synthesis.     

Insight into the studies of the practical use of microalgae in the former Soviet Union

Microalgae have been intensively cultivated and used in the national economy of the Soviet Union in Russia (Moscow, Leningrad, Pushcino, Krasnoyarsk, Irkutsk), the Ukraine, Byelorussia (Minsk), Azerbaijan (Baku), Uzbekistan (Tashkent), Latvia (Riga) and other former Soviet republics. The first studies on the practical use of microalgae started already at the beginning of last century and were connected with treatment of waste water in biological ponds. Ecophysiological studies of marine plankton algae in mono- and mixed cultures as well as in experimental systems with zooplankton organisms started at the end of the 1950s. In the 1960s, started to apply different equipments for cultivation of microalgae in open water basins and closed ecological systems. Research innovations were introduced in agriculture. The productivity of aquatic ecosystems and the distribution of energy within food chains were studied. Intensive research on microalgae continued, paying attention to the chemical composition, physiological and biochemical features. Nutrient supply appeared as one of the main problem for productivity of algal cultures, along with the procession, biochemistry of nutrients and nutrition value of organic matter produced by algae. The most attention was paid to the Chroococcales proteins and possibilities for their use in man-made closed ecological systems. The potential use of microalgae for regeneration of the atmosphere and purification of water in spacecrafts was studied. During the 1970s attention was paid to the role of algae in self-purification processes and biodegradation of surface-active substances in water bodies. Research in microalgae as bioindicators for the assessment of environment quality of aquatic ecosystems and as test objects for biotesting of natural and waste waters was conducted from the 1970s to 1980s.     

Characterization of the channel constriction allowing the access of the substrate to the active site of yeast oxidosqualene cyclase

In oxidosqualene cyclases (OSCs), an enzyme which has been extensively studied as a target for hypocholesterolemic or antifungal drugs, a lipophilic channel connects the surface of the protein with the active site cavity. Active site and channel are separated by a narrow constriction operating as a mobile gate for the substrate passage. In Saccharomyces cerevisiae OSC, two aminoacidic residues of the channel/constriction apparatus, Ala525 and Glu526, were previously showed as critical for maintaining the enzyme functionality. In this work sixteen novel mutants, each bearing a substitution at or around the channel constrictions, were tested for their enzymatic activity. Modelling studies showed that the most functionality-lowering substitutions deeply alter the H-bond network involving the channel/constriction apparatus. A rotation of Tyr239 is proposed as part of the mechanism permitting the access of the substrate to the active site. The inhibition of OSC by squalene was used as a tool for understanding whether the residues under study are involved in a pre-catalytic selection and docking of the substrate oxidosqualene.     

Serum chemistry of the minke whale from the northeastern Atlantic

Serum samples were collected from 42 harpooned minke whales (Balaenoptera acutorostrata) during commercial whaling off the coast of northern Norway (1997 and 1998) and analyzed for serum chemistry parameters in order to find clinical reference values for the northeastern Atlantic stock of this species. Mean and median values, as well as standard deviation and 90% central range, are presented for 28 different serum chemistry parameters. Lipemia is a common finding in marine mammals such as the minke whale, and chemical analysis of lipemic serum samples may produce artifacts. We found statistically significant elevated values of total protein, globulin, aspartate aminotransferase (AST), alanine aminotransferase (ALT), sodium and chloride in strongly-lipemic compared to non-lipemic samples, all which may be artifacts due to interference of lipids with the methods used for analysis. In addition, we found significantly elevated levels of creatin kinase, lactate dehydrogenase (LDH), urea, uric acid and triglycerides, as well as a decrease in creatinine in the strongly lipemic samples. Reanalyzing serum samples after twelve mo storage at -20 C (n = 13) revealed reduction in the serum concentration of the enzymes ALT (42%), alkaline phosphatase (ALP; 10%), LDH (19%), gamma glutamyl transferase (17%) and amylase (11%), as well as for triglycerides (9%) and non-esterified fatty acids (16%). It is crucial that serum chemistry analysis is performed without delay after sampling. Possible changes in the values of some parameters due to the presence of high amounts of lipids or long term storage of samples must be considered when interpreting results from serum chemistry analysis in these animals.     

弗特吉族在中国的发现及其意义

在连续数年的稀有濒危植物调研中,发现特产于江苏宜兴的小叶金缕梅实属一误订。该植物花两性,绝无花瓣,故可以肯定是金缕梅亚科中我国唯一缺少的弗特吉族植物。弗特吉族在中国的发现,使中国成为世界上唯一拥有该亚科五个族的国家,证明中国是世界金缕梅亚科的多样性中心,填补了该族在东亚分布的空白,为中国新生代植物研究和对金缕梅科以及被子植物的系统学研究提供了不可缺少的活材料。     

Doxorubicin inhibits the phosphate-transport protein reconstituted in liposomes. A study on the mechanism of the inhibition

Using Thr(P)-inhibitor-1 and Ser(P)-casein as substrates, studies on the activation of calcineurin purified from bovine brain have been carried out. The phosphatase requires the synergistic action of Ca2+, calmodulin and another divalent cation (Mg2+, Mn2+, Co2+ or Ni2+, but not Zn2+) for full expression of its activity. Ca2+ and Ca2+ X calmodulin act as allosteric activators to transform the phosphatase to a relaxed conformation, while Mg2+ acts solely as a cofactor for the catalytic action of the enzyme. In addition to their function as cofactors for catalysis, transition metal ions can also substitute for Ca2+ as allosteric activators. Ca2+ and calmodulin exert their activating effects mainly by increasing the Vm of the phosphatase reaction with little effect on the Km values for the substrates or on the KA values for the divalent cation cofactors. The predominant factor in dictating the catalytic properties of calcineurin is the divalent cation cofactor. For example, with Mg2+ as a cofactor, the phosphatase exhibits an optimum around pH 8.0-8.5; while with a transition metal ion as a cofactor, the optimum is around pH 7.0-7.5, regardless of whether Thr(P)-inhibitor-1 or Ser(P)-casein serves as a substrate, in the absence or the presence of Ca2+ X calmodulin.     

From the sequence to the superstructural properties of DNAs

A theoretical model for predicting intrinsic and induced DNA superstructures as well as their thermodynamic properties is presented. Intrinsic sequence-dependent superstructures are evaluated by integrating local deviations from the canonical B-DNA of the different dinucleotide steps. Induced superstructures are obtained by adopting the principle of minimum deformation free energy, evaluated in the Fourier space, in the framework of first-order elasticity. Finally dinucleotide stacking energies and melting temperatures are considered to account for local flexibility. In fact the two scales are strongly correlated. The model works very satisfactorily in predicting the sequence-dependent effects on the DNA experimental behavior, such as the gel electrophoresis retardation, the writhe transitions in topologically constrained domains, the thermodynamic constants of circularization reactions as well as the nucleosome thermodynamic stability constants.