A genome-wide integrative study of microRNAs in human liver

Abstract: Background: Recent studies have illuminated the diversity of roles for microRNAs in cellular, developmental, and pathophysiological processes. The study of microRNAs in human liver tissue promises to clarify the therapeutic and diagnostic value of this important regulatory mechanism of gene expression. Results: We conducted genome-wide profiling of microRNA expression in liver and performed an integrative analysis with previously collected genotype and transcriptome data. We report here that the Very Important Pharmacogenes (VIP Genes), comprising of genes of particular relevance for pharmacogenomics, are under substantial microRNA regulatory effect in the liver. We set out to elucidate the genetic basis of microRNA expression variation in liver and mapped microRNA expression to genomic loci as microRNA expression quantitative trait loci (miR-eQTLs). We identified common variants that attain genome-wide significant association (p < 10[-10]) with microRNA expression. We also found that the miR-eQTLs are significantly more likely to predict mRNA levels at a range of p-value thresholds than a random set of allele frequency matched SNPs, showing the functional effect of these loci on the transcriptome. Finally, we show that a large number of miR-eQTLs overlap with SNPs reproducibly associated with complex traits from the NHGRI repository of published genome-wide association studies as well as variants from a comprehensive catalog of manually curated pharmacogenetic associations. Conclusion: Our study provides important insights into the genomic architecture of gene regulation in a vital human organ, with important implications for our understanding of disease pathogenesis, therapeutic outcome, and other complex human phenotypes

Preclinical discovery of candidate genes to guide pharmacogenetics during phase I development: the example of the novel anticancer agent ABT-751

ABT-751, a novel orally available antitubulin agent, is mainly eliminated as inactive glucuronide (ABT-751G) and sulfate (ABT-751S) conjugates. We performed a pharmacogenetic investigation of ABT-751 pharmacokinetics using in-vitro data to guide the selection of genes for genotyping in a phase I trial of ABT-751

Identification, Replication, and Functional Fine-Mapping of Expression Quantitative Trait Loci in Primary Human Liver Tissue

The discovery of expression quantitative trait loci (“eQTLs”) can help to unravel genetic contributions to complex traits. We identified genetic determinants of human liver gene expression variation using two independent collections of primary tissue profiled with Agilent (n = 206) and Illumina (n = 60) expression arrays and Illumina SNP genotyping (550K), and we also incorporated data from a published study (n = 266). We found that ∼30% of SNP-expression correlations in one study failed to replicate in either of the others, even at thresholds yielding high reproducibility in simulations, and we quantified numerous factors affecting reproducibility. Our data suggest that drug exposure, clinical descriptors, and unknown factors associated with tissue ascertainment and analysis have substantial effects on gene expression and that controlling for hidden confounding variables significantly increases replication rate. Furthermore, we found that reproducible eQTL SNPs were heavily enriched near gene starts and ends, and subsequently resequenced the promoters and 3′UTRs for 14 genes and tested the identified haplotypes using luciferase assays. For three genes, significant haplotype-specific in vitro functional differences correlated directly with expression levels, suggesting that many bona fide eQTLs result from functional variants that can be mechanistically isolated in a high-throughput fashion. Finally, given our study design, we were able to discover and validate hundreds of liver eQTLs. Many of these relate directly to complex traits for which liver-specific analyses are likely to be relevant, and we identified dozens of potential connections with disease-associated loci. These included previously characterized eQTL contributors to diabetes, drug response, and lipid levels, and they suggest novel candidates such as a role for NOD2 expression in leprosy risk and C2orf43 in prostate cancer. In general, the work presented here will be valuable for future efforts to precisely identify and functionally characterize genetic contributions to a variety of complex traits

Metacognition in the process of education

This paper deals with different theoretical views and research regarding metacognition, its components and relations to cognition, conceptual discrepancy as well as opposing research results. Special attention was paid to the relation between metacognitive knowledge and the regulation of cognitive strategies. Reflexive awareness about personal cognitive processes is emphasized, but research discrepancies are apparent in regard to cognitive regulation. Research results focused on development of personal learning awareness and regulative skill involvement in the educational process (planning, monitoring and evaluating) are presented. A discussion was also focused on various views on relations between metacognition and the self which are of special importance for providing motivation in learning. Research data show that metacognitive awareness correlates with self. Metacognitive training affects development of the control experience and self-efficiency. The role of metacognition is emphasized as important for understanding relationship between cognition and motivation, which also affects learning self-regulation development. The paper emphasizes the significance of further study of metacognition and the possibilities for its use in the educational process. Research show that both metacognitive knowledge and regulation may be beneficial for: problem solving in learning processes, development of learning strategies and student achievement

Causes of learning problems in primary school students

Investigations were conducted on learning problems using the sample of eighth-grade students of primary school (N=335). The respondents opted for one or more than seven offered statements related to: insufficient previous knowledge, insufficient studying, teaching contents (extensive, difficult unintelligible), textbook and teacher’s method of presenting the contents. On the basis of the results obtained, one-third of students have problems in mastering teaching contents of foreign language, physics and chemistry, and about one-fourth in mastering those of history and mathematics. All the mentioned causes of problems are present in varying degrees in some school subjects. The causes of learning problems are markedly present in a larger number of school subjects and they are related to some characteristics of teaching contents. Respondents point out, to a large extent, that teaching contents of technical education are uninteresting. In addition, students’ responses indicate that it is necessary to improve the method for mastering the teaching contents in various school subjects i.e. methods applied in the teaching process. Subjective causes, as pointed out by students, are connected with some of the subjects they have characterized as the most difficult. Unintelligible textbook is stressed to the lowest extent as a cause of learning problems compared to other causes stated for the majority of school subjects

Orientations towards the goals of pupils and their importance for achieving success in learning

The starting point of this paper are two orientations towards goals that were identified in a large number of studies: orientations towards learning and orientations towards achievement. Social goals of pupils were especially discussed. There is the analysis of the relations of these orientations with success in learning, as well as with other variables related to personality and environment. Special treatment was given to the findings of empirical research indicating the possibility of existence of multiple orientations towards goals. That means that they can be in different mutual relations and in such a way exert different influence on the achievement of success in learning. Complementary effect of different goals enables flexible behavior of pupils in different situations, and coordination of different goals can be especially important for achieving success. Regarding the conceptualization of individual orientations, it was demonstrated how it is possible to treat separately both the different strivings within orientation towards achievement and orientation towards studying, and the different social goals of pupils. The characteristics of learning situation, as well as the way in which the pupil experiences the task of learning, are significant for the effect orientations can have on goals and on achievement of success in learning. Some recommendations for encouraging the pupil in teaching process are listed, as well as the implications for further research in this field

Learning approaches and studies of effect of environmental factors

There is a presentation of 3P model of learning (Presage-Process-Product), which comprises learning approaches placed in a wider context of the set of variables related to personality, environment, process and outcomes of learning. Three approaches to learning - surface, deep and achievement-oriented - consist of motives and the corresponding learning strategies. There is a discussion of the findings and implications of a great deal of research using the instruments based on this model. We analyzed research findings about the effect of instruction on learning approaches acquired by pupils, and especially students. It is shown how based on learning approach employed by pupils it is possible to draw conclusions about the quality of instruction. Testing the instruments on various samples indicates that the model is applicable in different cultures. Cross-cultural research opened up the problem of relation between memorising and understanding. Further research is necessary, both empirical and theoretical, that is, development of conceptualization of these constructs, and especially their role in education. Perspectives for further research also open up in the direction of studying various factors connected with personality and their relations with learning approaches. The role of learning approaches of teachers in developing the learning approaches of pupils is yet to be examined

Role of metacognitive processes in developing learning strategies

Within the context of effects that findings in the domain of cognitive psychology produce on the improvement of learning process in teaching, the results for examinations on student learning strategies and some of their implications were analyzed. Diverse methods for the operationalization of strategies, both cognitive and metacognitive, applied by students are featured. It is demonstrated that engagement of metacognitive processes is of crucial importance, firstly for developing efficient learning strategies and then for achieving better quality outcomes of educational process. Metacognition is treated in some studies as a process parallel to cognition and accordingly, distinction is made between cognitive and metacognitive learning strategies. But metacognitive processes are also often treated as intrinsic factors acting in the process of developing and using cognitive strategies in learning and they determine features and quality of those strategies and their effects. Some prospects for further intervening trends in the process of teaching are presented using the findings. It is emphasized that influence exerted by social environment i.e. school setting where the process of learning is going on can not be disregarded

Self-regulation in learning: Application of strategies and roles of orientation towards goals

This paper presents different views on self-regulation in the process of learning. What is shown is the model in which self-regulation is treated as the interaction of processes connected to personality, behavioral and contextual processes. The regulation processes are organized in several phases, and within each phase self-regulatory activities are structured in different fields. Special attention is paid to the application of strategies - cognitive, meta-cognitive, motivational and strategies of resource management. As a critical component of self-regulation, the monitoring and the steps it consists of were discussed in more detail. The emphasis is on the role of feedback in monitoring, as well as on the wider significance it has for self-regulation in the process of learning. Since orientation towards the goal is considered an essential aspect of self-regulation, what was performed was the analysis of the results and implications of different researches of the relation of pupils’ orientations towards the goals with regulation of the process of learning. The possibilities for encouraging self-regulation in the tuition process were considered. By enabling pupils to make decisions, set their own goals, perform the choice and plan and organize their activities, the development of self-regulation and autonomy is encouraged. The guidelines for planning the training aimed towards the development of strategy behavior in pupils are stated. What is presented are the different methods which are applied within the model and interventions in tuition directed towards encouragement of self-regulation

General causality orientations and defensive attributions of failure on academic exam

Defensive behaviour after failure, such as denial of the responsibility for own achievement, reduces person’s openness for further learning and development and, thus, is undesirable in pedagogical practice. General causality orientations success-fully predict defensive behaviours after failure. Autonomous causality orientation implies behaviours motivated by personal growth and development, while controlling orientation purports ego-involved behaviours aimed at proving one's own self-worth. The research was conducted with the aim of testing two hypotheses (additive and synergistic) about the influence of general causality orientations and their combinations on defensive attribution of failure on the exam. After their faculty exam, N=158 psychology students answered questions about the expected grade and they filled out two questionnaires: Attribution of Success on the Test and General Causality Orientation Scale. The results showed that internal attribution of success is related to greater expected grade and higher autonomous causality orientation. External attribution was characteristic for individuals with high controlling causal orientation. It was confirmed that general causality orientations can predict the way a person perceives academic success. Thus, we give recommendations on how to support and encourage autonomous and discourage controlling behaviours of students