miRConnect 2.0: identification of oncogenic, antagonistic miRNA families in three human cancers

Abstract Background Based on their function in cancer micro(mi)RNAs are often grouped as either tumor suppressors or oncogenes. However, miRNAs regulate multiple tumor relevant signaling pathways raising the question whether two oncogenic miRNAs could be functional antagonists by promoting different steps in tumor progression. We recently developed a method to connect miRNAs to biological function by comparing miRNA and gene array expression data from the NCI60 cell lines without using miRNA target predictions (miRConnect). Results We have now extended this analysis to three primary human cancers (ovarian cancer, glioblastoma multiforme, and kidney renal clear cell carcinoma) available at the Cancer Genome Atlas (TCGA), and have correlated the expression of the clustered miRNAs with 158 oncogenic signatures (miRConnect 2.0). We have identified functionally antagonistic groups of miRNAs. One group (the agonists), which contains many of the members of the miR-17 family, correlated with c-Myc induced genes and E2F gene signatures. A group that was directly antagonistic to the agonists in all three primary cancers contains miR-221 and miR-222. Since both miR-17 ~ 92 and miR-221/222 are considered to be oncogenic this points to a functional antagonism of different oncogenic miRNAs. Analysis of patient data revealed that in certain patients agonistic miRNAs predominated, whereas in other patients antagonists predominated. In glioblastoma a high ratio of miR-17 to miR-221/222 was predictive of better overall survival suggesting that high miR-221/222 expression is more adverse for patients than high miR-17 expression. Conclusion miRConnect 2.0 is useful for identifying activities of miRNAs that are relevant to primary cancers. The new correlation data on miRNAs and mRNAs deregulated in three primary cancers are available at miRConnect.orghttp://deepblue.lib.umich.edu/bitstream/2027.42/112974/1/12864_2013_Article_4929.pd

Structure of MnO nanoparticles embedded into channel-type matrices

X-ray diffraction experiments were performed on MnO confined in mesoporous silica SBA-15 and MCM-41 matrices with different channel diameters. The measured patterns were analyzed by profile analysis and compared to numerical simulations of the diffraction from confined nanoparticles. From the lineshape and the specific shift of the diffraction reflections it was shown that the embedded objects form ribbon-like structures in the SBA-15 matrices with channels diameters of 47-87 {\AA}, and nanowire-like structures in the MCM-41 matrices with channels diameters of 24-35 {\AA}. In the latter case the confined nanoparticles appear to be narrower than the channel diameters. The physical reasons for the two different shapes of the confined nanoparticles are discussed.Comment: 8 pages, including 9 postscript figures, uses revtex4.cl

miRConnect: Identifying Effector Genes of miRNAs and miRNA Families in Cancer Cells

micro(mi)RNAs are small non-coding RNAs that negatively regulate expression of most mRNAs. They are powerful regulators of various differentiation stages, and the expression of genes that either negatively or positively correlate with expressed miRNAs is expected to hold information on the biological state of the cell and, hence, of the function of the expressed miRNAs. We have compared the large amount of available gene array data on the steady state system of the NCI60 cell lines to two different data sets containing information on the expression of 583 individual miRNAs. In addition, we have generated custom data sets containing expression information of 54 miRNA families sharing the same seed match. We have developed a novel strategy for correlating miRNAs with individual genes based on a summed Pearson Correlation Coefficient (sPCC) that mimics an in silico titration experiment. By focusing on the genes that correlate with the expression of miRNAs without necessarily being direct targets of miRNAs, we have clustered miRNAs into different functional groups. This has resulted in the identification of three novel miRNAs that are linked to the epithelial-to-mesenchymal transition (EMT) in addition to the known EMT regulators of the miR-200 miRNA family. In addition, an analysis of gene signatures associated with EMT, c-MYC activity, and ribosomal protein gene expression allowed us to assign different activities to each of the functional clusters of miRNAs. All correlation data are available via a web interface that allows investigators to identify genes whose expression correlates with the expression of single miRNAs or entire miRNA families. miRConnect.org will aid in identifying pathways regulated by miRNAs without requiring specific knowledge of miRNA targets

Endogenous insulin secretion in critically ill patients

1-pageGlucose-insulin system models can be used for improved glycemic control of critically ill patients. A key component of glucose-insulin models is pancreatic insulin secretion. There is limited data in the literature quantifying insulin secretion in critically ill patients at physiologic levels. This study presents a model pancreatic insulin secretion in critically ill patients based on data from a critically ill population

Quantum internal modes of solitons in 1d easy-plane antiferromagnet in strong magnetic field

In presence of a strong external magnetic field the dynamics of solitons in a one-dimensional easy-plane Heisenberg antiferromagnet exhibits a number of peculiarities. Dynamics of internal soliton degrees of freedom is essentially quantum, and they are strongly coupled to the "translational" mode of soliton movement. These peculiarities lead to considerable changes in the response functions of the system which can be detected experimentally.Comment: 8 pages, RevTeX, 6 figures, uses psfig.sty, submitted to PR

A circular RNA generated from an intron of the insulin gene controls insulin secretion.

Fine-tuning of insulin release from pancreatic β-cells is essential to maintain blood glucose homeostasis. Here, we report that insulin secretion is regulated by a circular RNA containing the lariat sequence of the second intron of the insulin gene. Silencing of this intronic circular RNA in pancreatic islets leads to a decrease in the expression of key components of the secretory machinery of β-cells, resulting in impaired glucose- or KCl-induced insulin release and calcium signaling. The effect of the circular RNA is exerted at the transcriptional level and involves an interaction with the RNA-binding protein TAR DNA-binding protein 43 kDa (TDP-43). The level of this circularized intron is reduced in the islets of rodent diabetes models and of type 2 diabetic patients, possibly explaining their impaired secretory capacity. The study of this and other circular RNAs helps understanding β-cell dysfunction under diabetes conditions, and the etiology of this common metabolic disorder

A circular RNA generated from an intron of the insulin gene controls insulin secretion

Fine-tuning of insulin release from pancreatic β-cells is essential to maintain blood glucose homeostasis. Here, we report that insulin secretion is regulated by a circular RNA containing the lariat sequence of the second intron of the insulin gene. Silencing of this intronic circular RNA in pancreatic islets leads to a decrease in the expression of key components of the secretory machinery of β-cells, resulting in impaired glucose- or KCl-induced insulin release and calcium signaling. The effect of the circular RNA is exerted at the transcriptional level and involves an interaction with the RNA-binding protein TAR DNA-binding protein 43 kDa (TDP-43). The level of this circularized intron is reduced in the islets of rodent diabetes models and of type 2 diabetic patients, possibly explaining their impaired secretory capacity. The study of this and other circular RNAs helps understanding β-cell dysfunction under diabetes conditions, and the etiology of this common metabolic disorder

Successful Versus Failed Adaptation to High-Fat Diet–Induced Insulin Resistance: The Role of IAPP-Induced β-Cell Endoplasmic Reticulum Stress

ObjectiveObesity is a known risk factor for type 2 diabetes. However, most obese individuals do not develop diabetes because they adapt to insulin resistance by increasing beta-cell mass and insulin secretion. Islet pathology in type 2 diabetes is characterized by beta-cell loss, islet amyloid derived from islet amyloid polypeptide (IAPP), and increased beta-cell apoptosis characterized by endoplasmic reticulum (ER) stress. We hypothesized that IAPP-induced ER stress distinguishes successful versus unsuccessful islet adaptation to insulin resistance.Research design and methodsTo address this, we fed wild-type (WT) and human IAPP transgenic (HIP) rats either 10 weeks of regular chow or a high-fat diet and prospectively examined the relations among beta-cell mass and turnover, beta-cell ER stress, insulin secretion, and insulin sensitivity.ResultsA high-fat diet led to comparable insulin resistance in WT and HIP rats. WT rats compensated with increased insulin secretion and beta-cell mass. In HIP rats, in contrast, neither beta-cell function nor mass compensated for the increased insulin demand, leading to diabetes. The failure to increase beta-cell mass in HIP rats was the result of ER stress-induced beta-cell apoptosis that increased in proportion to diet-induced insulin resistance.ConclusionsIAPP-induced ER stress distinguishes the successful versus unsuccessful islet adaptation to a high-fat diet in rats. These studies are consistent with the hypothesis that IAPP oligomers contribute to increased beta-cell apoptosis and beta-cell failure in humans with type 2 diabetes

An Unusual Topological Structure of the HIV-1 Rev Response Element

SummaryNuclear export of unspliced and singly spliced viral mRNA is a critical step in the HIV life cycle. The structural basis by which the virus selects its own mRNA among more abundant host cellular RNAs for export has been a mystery for more than 25 years. Here, we describe an unusual topological structure that the virus uses to recognize its own mRNA. The viral Rev response element (RRE) adopts an “A”-like structure in which the two legs constitute two tracks of binding sites for the viral Rev protein and position the two primary known Rev-binding sites ∼55 Å apart, matching the distance between the two RNA-binding motifs in the Rev dimer. Both the legs of the “A” and the separation between them are required for optimal RRE function. This structure accounts for the specificity of Rev for the RRE and thus the specific recognition of the viral RNA