A mathematical model for the adenylosuccinate synthetase reaction involved in purine biosynthesis

BACKGROUND: Development of the mathematical models that adequately describe biochemical reactions and molecular-genetic mechanisms is one of the most important tasks in modern bioinformatics. Because the enzyme adenylosuccinate synthetase (AdSS) has long been extensively studied, a wealth of kinetic data has been accumulated. RESULTS: We describe a mathematical model for the reaction catalyzed by AdSS. The model's parameters were fitted to experimental data obtained from published literature. The advantage of our model is that it includes relationships between the reaction rate, the concentrations of three substrates (GTP, IMP and ASP), the effects of five inhibitors (GMP, GDP, AMP, ASUC and SUCC), and the influence of Mg(2+ )ions. CONCLUSION: Our model describes the reaction catalyzed by AdSS as a fully random process. The model structure implies that each of the inhibitors included in it is only competitive to one of the substrates. The model was tested for adequacy using experimental data published elsewhere. The values obtained for the parameters are as follows: V(max )= 1.35·10(-3 )mM/min, Km(GTP )= 0.023 mM, Km(IMP )= 0.02 mM, Km(ASP )= 0.3 mM, Ki(GMP )= 0.024 mM, Ki(GDP )= 8·10(-3 )mM, Ki(AMP )= 0.01 mM, Ki(ASUC )= 7.5·10(-3 )mM, Ki(SUCC )= 8 mM, Km(Mg )= 0.08 mM

Science that "knows" and science that "asks"

Clinician-researchers and experimental scientists do not speak the same language; they have different professional environments and different end-points in their research. This creates considerable problems of comprehension and communication, which constitute a major drawback in multidisciplinary work such as translational medicine. A stereotypic representation of both these worlds is presented as a starting point to encourage debate on this issue

In the quest for new targets for pathogen eradication: the adenylosuccinate synthetase from the bacterium Helicobacter pylori

Adenylosuccinate synthetase (AdSS) is an enzyme at regulatory point of purine metabolism. In pathogenic organisms which utilise only the purine salvage pathway, AdSS asserts itself as a promising drug target. One of these organisms is Helicobacter pylori, a wide-spread human pathogen involved in the development of many diseases. The rate of H. pylori antibiotic resistance is on the increase, making the quest for new drugs against this pathogen more important than ever. In this context, we describe here the properties of H. pylori AdSS. This enzyme exists in a dimeric active form independently of the presence of its ligands. Its narrow stability range and pH-neutral optimal working conditions reflect the bacterium’s high level of adaptation to its living environment. Efficient inhibition of H. pylori AdSS with hadacidin and adenylosuccinate gives hope of finding novel drugs that aim at eradicating this dangerous pathogen

Undergraduate medical research: the student perspective

Background: Research training is essential in a modern undergraduate medical curriculum. Our evaluation aimed to (a) gauge students’ awareness of research activities, (b) compare students’ perceptions of their transferable and research-specific skills competencies, (c) determine students’ motivation for research and (d) obtain students’ personal views on doing research. Methods: Undergraduate medical students (N=317) completed a research skills questionnaire developed by the Centre for Excellence in Teaching and Learning in Applied Undergraduate Research Skills (CETL-AURS) at Reading University. The questionnaire assessed students’ transferable skills, research-specific skills (e.g., study design, data collection and data analysis), research experience and attitude and motivation towards doing research. Results: The majority of students are motivated to pursue research. Graduate entrants and male students appear to be the most confident regarding their research skills competencies. Although all students recognise the role of research in medical practice, many are unaware of the medical research activities or successes within their university. Of those who report no interest in a career incorporating research, a common perception was that researchers are isolated from patients and clinical practice. Discussion: Students have a narrow definition of research and what it entails. An explanation for why research competence does not align more closely with research motivation is derived from students’ lack of understanding of the concept of translational research, as well as a lack of awareness of the research activity being undertaken by their teachers and mentors. We plan to address this with specific research awareness initiatives

Individual characteristics and student's engagement in scientific research : a cross-sectional study

Background: In light of the increasing recognition of the importance of physician scientists, and given the association between undergraduate research experiences with future scientific activity, it is important to identify and understand variables related to undergraduate student’s decision to engage in scientific research activities. The present study assessed the influence of individual characteristics, including personality traits and socio-demographic characteristics, on voluntary engagement in scientific research of undergraduate medical students. Methods: For this study, all undergraduate students and alumni of the School of Health Sciences in Minho, Portugal were invited to participate in a survey about voluntary engagement in scientific research activities. Data were available on socio-demographic, personality and university admission variables, as part of an ongoing longitudinal study. A regression model was used to compare (1) engaged with (2) not engaged students. A classification and regression tree model was used to compare students engaged in (3) elective curricular research (4) and extra-curricular research. Results: A total of 466 students (88%) answered the survey. A complete set of data was available for 435 students (83%).Higher scores in admission grade point average and the personality dimensions of “openness to experience” and “conscientiousness” increased chances of engagement. Higher “extraversion” scores had the opposite effect. Male undergraduate students were two times more likely than females to engage in curricular elective scientific research and were also more likely to engage in extra-curricular research activities. Conclusions: This study demonstrated that student’s grade point average and individual characteristics, like gender, openness and consciousness have a unique and statistically significant contribution to student’s involvement in undergraduate scientific research activities.Fundação para a Ciência e a Tecnologia (FCT) - PTDC/ESC/65116/200

Conditional Ablation of Ezh2 in Murine Hearts Reveals Its Essential Roles in Endocardial Cushion Formation, Cardiomyocyte Proliferation and Survival

Ezh2 is a histone trimethyltransferase that silences genes mainly via catalyzing trimethylation of histone 3 lysine 27 (H3K27Me3). The role of Ezh2 as a regulator of gene silencing and cell proliferation in cancer development has been extensively investigated; however, its function in heart development during embryonic cardiogenesis has not been well studied. In the present study, we used a genetically modified mouse system in which Ezh2 was specifically ablated in the mouse heart. We identified a wide spectrum of cardiovascular malformations in the Ezh2 mutant mice, which collectively led to perinatal death. In the Ezh2 mutant heart, the endocardial cushions (ECs) were hypoplastic and the endothelial-to-mesenchymal transition (EMT) process was impaired. The hearts of Ezh2 mutant mice also exhibited decreased cardiomyocyte proliferation and increased apoptosis. We further identified that the Hey2 gene, which is important for cardiomyocyte proliferation and cardiac morphogenesis, is a downstream target of Ezh2. The regulation of Hey2 expression by Ezh2 may be independent of Notch signaling activity. Our work defines an indispensible role of the chromatin remodeling factor Ezh2 in normal cardiovascular development