An integrative approach to characterize disease-specific pathways and their coordination: a case study in cancer

BACKGROUND: The most common application of microarray technology in disease research is to identify genes differentially expressed in disease versus normal tissues. However, it is known that, in complex diseases, phenotypes are determined not only by genes, but also by the underlying structure of genetic networks. Often, it is the interaction of many genes that causes phenotypic variations. RESULTS: In this work, using cancer as an example, we develop graph-based methods to integrate multiple microarray datasets to discover disease-related co-expression network modules. We propose an unsupervised method that take into account both co-expression dynamics and network topological information to simultaneously infer network modules and phenotype conditions in which they are activated or de-activated. Using our method, we have discovered network modules specific to cancer or subtypes of cancers. Many of these modules are consistent with or supported by their functional annotations or their previously known involvement in cancer. In particular, we identified a module that is predominately activated in breast cancer and is involved in tumor suppression. While individual components of this module have been suggested to be associated with tumor suppression, their coordinated function has never been elucidated. Here by adopting a network perspective, we have identified their interrelationships and, particularly, a hub gene PDGFRL that may play an important role in this tumor suppressor network. CONCLUSION: Using a network-based approach, our method provides new insights into the complex cellular mechanisms that characterize cancer and cancer subtypes. By incorporating co-expression dynamics information, our approach can not only extract more functionally homogeneous modules than those based solely on network topology, but also reveal pathway coordination beyond co-expression

The Astropy Problem

The Astropy Project (http://astropy.org) is, in its own words, "a community effort to develop a single core package for Astronomy in Python and foster interoperability between Python astronomy packages." For five years this project has been managed, written, and operated as a grassroots, self-organized, almost entirely volunteer effort while the software is used by the majority of the astronomical community. Despite this, the project has always been and remains to this day effectively unfunded. Further, contributors receive little or no formal recognition for creating and supporting what is now critical software. This paper explores the problem in detail, outlines possible solutions to correct this, and presents a few suggestions on how to address the sustainability of general purpose astronomical software

Neuronal MicroRNA Deregulation in Response to Alzheimer's Disease Amyloid-β

Normal brain development and function depends on microRNA (miRNA) networks to fine tune the balance between the transcriptome and proteome of the cell. These small non-coding RNA regulators are highly enriched in brain where they play key roles in neuronal development, plasticity and disease. In neurodegenerative disorders such as Alzheimer's disease (AD), brain miRNA profiles are altered; thus miRNA dysfunction could be both a cause and a consequence of disease. Our study dissects the complexity of human AD pathology, and addresses the hypothesis that amyloid-β (Aβ) itself, a known causative factor of AD, causes neuronal miRNA deregulation, which could contribute to the pathomechanisms of AD. We used sensitive TaqMan low density miRNA arrays (TLDA) on murine primary hippocampal cultures to show that about half of all miRNAs tested were down-regulated in response to Aβ peptides. Time-course assays of neuronal Aβ treatments show that Aβ is in fact a powerful regulator of miRNA levels as the response of certain mature miRNAs is extremely rapid. Bioinformatic analysis predicts that the deregulated miRNAs are likely to affect target genes present in prominent neuronal pathways known to be disrupted in AD. Remarkably, we also found that the miRNA deregulation in hippocampal cultures was paralleled in vivo by a deregulation in the hippocampus of Aβ42-depositing APP23 mice, at the onset of Aβ plaque formation. In addition, the miRNA deregulation in hippocampal cultures and APP23 hippocampus overlaps with those obtained in human AD studies. Taken together, our findings suggest that neuronal miRNA deregulation in response to an insult by Aβ may be an important factor contributing to the cascade of events leading to AD

Impact of Host Genes and Strand Selection on miRNA and miRNA* Expression

Dysregulation of miRNAs expression plays a critical role in the pathogenesis of genetic, multifactorial disorders and in human cancers. We exploited sequence, genomic and expression information to investigate two main aspects of post-transcriptional regulation in miRNA biogenesis, namely strand selection regulation and expression relationships between intragenic miRNAs and host genes. We considered miRNAs expression profiles, measured in five sizeable microarray datasets, including samples from different normal cell types and tissues, as well as different tumours and disease states. First, the study of expression profiles of “sister” miRNA pairs (miRNA/miRNA*, 5′ and 3′ strands of the same hairpin precursor) showed that the strand selection is highly regulated since it shows tissue-/cell-/condition-specific modulation. We used information about the direction and the strength of the strand selection bias to perform an unsupervised cluster analysis for the sample classification evidencing that is able to distinguish among different tissues, and sometimes between normal and malignant cells. Then, considering a minimum expression threshold, in few miRNA pairs only one mature miRNA is always present in all considered cell types, whereas the majority of pairs were concurrently expressed in some cell types and alternatively in others. In a significant fraction of concurrently expressed pairs, the major and the minor forms found at comparable levels may contribute to post-transcriptional gene silencing, possibly in a coordinate way. In the second part of the study, the behaved tendency to co-expression of intragenic miRNAs and their “host” mRNA genes was confuted by expression profiles examination, suggesting that the expression profile of a given host gene can hardly be a good estimator of co-transcribed miRNA(s) for post-transcriptional regulatory networks inference. Our results point out the regulatory importance of post-transcriptional phases of miRNAs biogenesis, reinforcing the role of such layer of miRNA biogenesis in miRNA-based regulation of cell activities

The MicroRNA and MessengerRNA Profile of the RNA-Induced Silencing Complex in Human Primary Astrocyte and Astrocytoma Cells

GW/P bodies are cytoplasmic ribonucleoprotein-rich foci involved in microRNA (miRNA)-mediated messenger RNA (mRNA) silencing and degradation. The mRNA regulatory functions within GW/P bodies are mediated by GW182 and its binding partner hAgo2 that bind miRNA in the RNA-induced silencing complex (RISC). To date there are no published reports of the profile of miRNA and mRNA targeted to the RISC or a comparison of the RISC-specific miRNA/mRNA profile differences in malignant and non-malignant cells.RISC mRNA and miRNA components were profiled by microarray analysis of malignant human U-87 astrocytoma cells and its non-malignant counterpart, primary human astrocytes. Total cell RNA as well as RNA from immunoprecipitated RISC was analyzed. The novel findings were fourfold: (1) miRNAs were highly enriched in astrocyte RISC compared to U-87 astrocytoma RISC, (2) astrocytoma and primary astrocyte cells each contained unique RISC miRNA profiles as compared to their respective cellular miRNA profiles, (3) miR-195, 10b, 29b, 19b, 34a and 455-3p levels were increased and the miR-181b level was decreased in U-87 astrocytoma RISC as compared to astrocyte RISC, and (4) the RISC contained decreased levels of mRNAs in primary astrocyte and U-87 astrocytoma cells.The observation that miR-34a and miR-195 levels were increased in the RISC of U-87 astrocytoma cells suggests an oncogenic role for these miRNAs. Differential regulation of mRNAs by specific miRNAs is evidenced by the observation that three miR34a-targeted mRNAs and two miR-195-targeted mRNAs were downregulated while one miR-195-targeted mRNA was upregulated. Biological pathway analysis of RISC mRNA components suggests that the RISC plays a pivotal role in malignancy and other conditions. This study points to the importance of the RISC and ultimately GW/P body composition and function in miRNA and mRNA deregulation in astrocytoma cells and possibly in other malignancies

X chromosome inactivation does not necessarily determine the severity of the phenotype in Rett syndrome patients

Rett syndrome (RTT) is a severe neurological disorder usually caused by mutations in the MECP2 gene. Since the MECP2 gene is located on the X chromosome, X chromosome inactivation (XCI) could play a role in the wide range of phenotypic variation of RTT patients; however, classical methylation-based protocols to evaluate XCI could not determine whether the preferentially inactivated X chromosome carried the mutant or the wild-type allele. Therefore, we developed an allele-specific methylation-based assay to evaluate methylation at the loci of several recurrent MECP2 mutations. We analyzed the XCI patterns in the blood of 174 RTT patients, but we did not find a clear correlation between XCI and the clinical presentation. We also compared XCI in blood and brain cortex samples of two patients and found differences between XCI patterns in these tissues. However, RTT mainly being a neurological disease complicates the establishment of a correlation between the XCI in blood and the clinical presentation of the patients. Furthermore, we analyzed MECP2 transcript levels and found differences from the expected levels according to XCI. Many factors other than XCI could affect the RTT phenotype, which in combination could influence the clinical presentation of RTT patients to a greater extent than slight variations in the XCI pattern

Lawson criterion for ignition exceeded in an inertial fusion experiment

For more than half a century, researchers around the world have been engaged in attempts to achieve fusion ignition as a proof of principle of various fusion concepts. Following the Lawson criterion, an ignited plasma is one where the fusion heating power is high enough to overcome all the physical processes that cool the fusion plasma, creating a positive thermodynamic feedback loop with rapidly increasing temperature. In inertially confined fusion, ignition is a state where the fusion plasma can begin "burn propagation" into surrounding cold fuel, enabling the possibility of high energy gain. While "scientific breakeven" (i.e., unity target gain) has not yet been achieved (here target gain is 0.72, 1.37 MJ of fusion for 1.92 MJ of laser energy), this Letter reports the first controlled fusion experiment, using laser indirect drive, on the National Ignition Facility to produce capsule gain (here 5.8) and reach ignition by nine different formulations of the Lawson criterion