Structural Comparison of Human Mammalian Ste20-Like Kinases

BACKGROUND: The serine/threonine mammalian Ste-20 like kinases (MSTs) are key regulators of apoptosis, cellular proliferation as well as polarization. Deregulation of MSTs has been associated with disease progression in prostate and colorectal cancer. The four human MSTs are regulated differently by C-terminal regions flanking the catalytic domains. PRINCIPAL FINDINGS: We have determined the crystal structure of kinase domain of MST4 in complex with an ATP-mimetic inhibitor. This is the first structure of an inactive conformation of a member of the MST kinase family. Comparison with active structures of MST3 and MST1 revealed a dimeric association of MST4 suggesting an activation loop exchanged mechanism of MST4 auto-activation. Together with a homology model of MST2 we provide a comparative analysis of the kinase domains for all four members of the human MST family. SIGNIFICANCE: The comparative analysis identified new structural features in the MST ATP binding pocket and has also defined the mechanism for autophosphorylation. Both structural features may be further explored for inhibitors design. ENHANCED VERSION: This article can also be viewed as an enhanced version in which the text of the article is integrated with interactive 3D representations and animated transitions. Please note that a web plugin is required to access this enhanced functionality. Instructions for the installation and use of the web plugin are available in Text S1

Cancer Biomarker Discovery: The Entropic Hallmark

Background: It is a commonly accepted belief that cancer cells modify their transcriptional state during the progression of the disease. We propose that the progression of cancer cells towards malignant phenotypes can be efficiently tracked using high-throughput technologies that follow the gradual changes observed in the gene expression profiles by employing Shannon's mathematical theory of communication. Methods based on Information Theory can then quantify the divergence of cancer cells' transcriptional profiles from those of normally appearing cells of the originating tissues. The relevance of the proposed methods can be evaluated using microarray datasets available in the public domain but the method is in principle applicable to other high-throughput methods. Methodology/Principal Findings: Using melanoma and prostate cancer datasets we illustrate how it is possible to employ Shannon Entropy and the Jensen-Shannon divergence to trace the transcriptional changes progression of the disease. We establish how the variations of these two measures correlate with established biomarkers of cancer progression. The Information Theory measures allow us to identify novel biomarkers for both progressive and relatively more sudden transcriptional changes leading to malignant phenotypes. At the same time, the methodology was able to validate a large number of genes and processes that seem to be implicated in the progression of melanoma and prostate cancer. Conclusions/Significance: We thus present a quantitative guiding rule, a new unifying hallmark of cancer: the cancer cell's transcriptome changes lead to measurable observed transitions of Normalized Shannon Entropy values (as measured by high-throughput technologies). At the same time, tumor cells increment their divergence from the normal tissue profile increasing their disorder via creation of states that we might not directly measure. This unifying hallmark allows, via the the Jensen-Shannon divergence, to identify the arrow of time of the processes from the gene expression profiles, and helps to map the phenotypical and molecular hallmarks of specific cancer subtypes. The deep mathematical basis of the approach allows us to suggest that this principle is, hopefully, of general applicability for other diseases

The genus Seseli L.: A comprehensive review on traditional uses, phytochemistry, and pharmacological properties

Introduction: The present article is the first comprehensive review of Seseli L. species. Seseli is one of the largest genera of the Apiaceae, and some species have been used in traditional medicine and foods besides their medicinal importance. This review aims to provide a comprehensive and critical appraisal of the past and present medicinal uses of Seseli species with their relevant bioactivity. This review also brings a new perspective in all aspects and emphasizes the importance of these species. Methodology: Mainly electronic databases were used as the primary sources for screening related articles and applying related search terms. Results: To date, the Seseli species have no or little attention and few phytochemical and pharmacological studies. Previous phytochemical investigations have confirmed that some species have mainly essential oils and coumarins. This review has also been established by reporting on the pharmacological activities of Seseli species. The genus Seseli has been reported as a good source of coumarins (especially anomalin, and osthol), which may be considered a chemotaxonomic marker. Conclusion: The literature available to date on the genus Seseli partially confirms the basis for some of the traditional uses of this genus and its remarkable pharmacological effects. The Seseli species has proven to be a good source of coumarins, especially pyranocoumarins, like anomalin. However, the uses of Seseli species to treat various diseases need different pharmacological studies before applying or starting clinical trials

Effects of antepartum education on worries about labor and mode of delivery

PMID = 3205083