A fuzzy method for RNA-Seq differential expression analysis in presence of multireads

Background: When the reads obtained from high-throughput RNA sequencing are mapped against a reference database, a significant proportion of them - known as multireads - can map to more than one reference sequence. These multireads originate from gene duplications, repetitive regions or overlapping genes. Removing the multireads from the mapping results, in RNA-Seq analyses, causes an underestimation of the read counts, while estimating the real read count can lead to false positives during the detection of differentially expressed sequences. Results: We present an innovative approach to deal with multireads and evaluate differential expression events, entirely based on fuzzy set theory. Since multireads cause uncertainty in the estimation of read counts during gene expression computation, they can also influence the reliability of differential expression analysis results, by producing false positives. Our method manages the uncertainty in gene expression estimation by defining the fuzzy read counts and evaluates the possibility of a gene to be differentially expressed with three fuzzy concepts: over-expression, same-expression and under-expression. The output of the method is a list of differentially expressed genes enriched with information about the uncertainty of the results due to the multiread presence. We have tested the method on RNA-Seq data designed for case-control studies and we have compared the obtained results with other existing tools for read count estimation and differential expression analysis. Conclusions: The management of multireads with the use of fuzzy sets allows to obtain a list of differential expression events which takes in account the uncertainty in the results caused by the presence of multireads. Such additional information can be used by the biologists when they have to select the most relevant differential expression events to validate with laboratory assays. Our method can be used to compute reliable differential expression events and to highlight possible false positives in the lists of differentially expressed genes computed with other tools

TRIM8 Blunts the Pro-proliferative Action of ΔNp63α in a p53 Wild-Type Background

The p53 gene family network plays a pivotal role in the control of many biological processes and therefore the right balance between the pro-apoptotic and pro-survival isoforms is key to maintain cellular homeostasis. The stability of the p53 tumor suppressor protein and that of oncogenic ΔNp63α, is crucial to control cell proliferation. The aberrant expression of p53 tumor suppressor protein and oncogenic ΔNp63α contributes to tumorigenesis and significantly affects anticancer drug response. Recently, we demonstrated that TRIM8 increases p53 stability, potentiating its tumor suppressor activity. In this paper, we show that TRIM8 simultaneously reduces the level of the pro-proliferative ΔNp63α protein, in both a proteasomal and caspase-1 dependent way, thereby playing a critical role in the cellular response to DNA damaging agents. Moreover, we provided evidence that ΔNp63α in turn, suppresses TRIM8 gene expression by preventing p53-mediated transactivation of TRIM8, therefore suggesting the existence of a negative feedback loop. These findings indicate that TRIM8 exerts its anticancer power through a joint action that provides on one hand, the activation of the p53 tumor suppressor role, and on the other the quenching of the oncogenic ΔNp63α protein activity. The enhancement of TRIM8 activity may offer therapeutic benefits and improve the management of chemoresistant tumors

Whole transcriptome profiling of Late-Onset Alzheimer's Disease patients provides insights into the molecular changes involved in the disease

Alzheimer's Disease (AD) is the most common cause of dementia affecting the elderly population worldwide. We have performed a comprehensive transcriptome profiling of Late-Onset AD (LOAD) patients using second generation sequencing technologies, identifying 2,064 genes, 47 lncRNAs and 4 miRNAs whose expression is specifically deregulated in the hippocampal region of LOAD patients. Moreover, analyzing the hippocampal, temporal and frontal regions from the same LOAD patients, we identify specific sets of deregulated miRNAs for each region, and we confirm that the miR-132/212 cluster is deregulated in each of these regions in LOAD patients, consistent with these miRNAs playing a role in AD pathogenesis. Notably, a luciferase assay indicates that miR-184 is able to target the 3'UTR NR4A2 - which is known to be involved in cognitive functions and long-term memory and whose expression levels are inversely correlated with those of miR-184 in the hippocampus. Finally, RNA editing analysis  reveals a general RNA editing decrease in LOAD hippocampus, with 14 recoding sites significantly and differentially edited in 11 genes. Our data underline specific transcriptional changes in LOAD brain and provide an important source of information for understanding the molecular changes characterizing LOAD progression

Dakwah Dalam Membangun Etika Kerukunan Hidup Umat Beragama

Indonesia is multi-ethnics, culture and religions,require normative values to regulate social relations.Normative values on religion, social values and moresthat have been prevailing in the community, is thebasis for building a culture of inter-religious relations.Pancasila and the 1945‟s Constitution is a collectiveagreement in regulating the society and the state.National unity took place in the community where thevalues of religion has lived and practiced. Religiousdiversity has become a reality of history and they havebeen living side by side. Today, Da‟wah activities inbuilding awareness in the practice of religion amongthe other religious communities, is needed. Therefore,the practice of the “inclusive religion” should beapplied

p53FamTaG: a database resource of human p53, p63 and p73 direct target genes combining in silico prediction and microarray data

<p>Abstract</p> <p>Background</p> <p>The p53 gene family consists of the three genes p53, p63 and p73, which have polyhedral non-overlapping functions in pivotal cellular processes such as DNA synthesis and repair, growth arrest, apoptosis, genome stability, angiogenesis, development and differentiation. These genes encode sequence-specific nuclear transcription factors that recognise the same responsive element (RE) in their target genes. Their inactivation or aberrant expression may determine tumour progression or developmental disease. The discovery of several protein isoforms with antagonistic roles, which are produced by the expression of different promoters and alternative splicing, widened the complexity of the scenario of the transcriptional network of the p53 family members. Therefore, the identification of the genes transactivated by p53 family members is crucial to understand the specific role for each gene in cell cycle regulation. We have combined a genome-wide computational search of p53 family REs and microarray analysis to identify new direct target genes. The huge amount of biological data produced has generated a critical need for bioinformatic tools able to manage and integrate such data and facilitate their retrieval and analysis.</p> <p>Description</p> <p>We have developed the p53FamTaG database (p53 FAMily TArget Genes), a modular relational database, which contains p53 family direct target genes selected in the human genome searching for the presence of the REs and the expression profile of these target genes obtained by microarray experiments. p53FamTaG database also contains annotations of publicly available databases and links to other experimental data.</p> <p>The genome-wide computational search of the REs was performed using PatSearch, a pattern-matching program implemented in the DNAfan tool. These data were integrated with the microarray results we produced from the overexpression of different isoforms of p53, p63 and p73 stably transfected in isogenic cell lines, allowing the comparative study of the transcriptional activity of all the proteins in the same cellular background.</p> <p>p53FamTaG database is available free at <url>http://www2.ba.itb.cnr.it/p53FamTaG/</url></p> <p>Conclusion</p> <p>p53FamTaG represents a unique integrated resource of human direct p53 family target genes that is extensively annotated and provides the users with an efficient query/retrieval system which displays the results of our microarray experiments and allows the export of RE sequences. The database was developed for supporting and integrating high-throughput <it>in silico</it> and experimental analyses and represents an important reference source of knowledge for research groups involved in the field of oncogenesis, apoptosis and cell cycle regulation.</p

TRIM Proteins in Colorectal Cancer: TRIM8 as a Promising Therapeutic Target in Chemo Resistance

Colorectal cancer (CRC) represents one of the most widespread forms of cancer in the population and, as all malignant tumors, often develops resistance to chemotherapies with consequent tumor growth and spreading leading to the patient's premature death. For this reason, a great challenge is to identify new therapeutic targets, able to restore the drugs sensitivity of cancer cells. In this review, we discuss the role of TRIpartite Motifs (TRIM) proteins in cancers and in CRC chemoresistance, focusing on the tumor-suppressor role of TRIM8 protein in the reactivation of the CRC cells sensitivity to drugs currently used in the clinical practice. Since the restoration of TRIM8 protein levels in CRC cells recovers chemotherapy response, it may represent a new promising therapeutic target in the treatment of CRC

TRIM Proteins in Colorectal Cancer: TRIM8 as a Promising Therapeutic Target in Chemo Resistance

Colorectal cancer (CRC) represents one of the most widespread forms of cancer in the population and, as all malignant tumors, often develops resistance to chemotherapies with consequent tumor growth and spreading leading to the patient’s premature death. For this reason, a great challenge is to identify new therapeutic targets, able to restore the drugs sensitivity of cancer cells. In this review, we discuss the role of TRIpartite Motifs (TRIM) proteins in cancers and in CRC chemoresistance, focusing on the tumor-suppressor role of TRIM8 protein in the reactivation of the CRC cells sensitivity to drugs currently used in the clinical practice. Since the restoration of TRIM8 protein levels in CRC cells recovers chemotherapy response, it may represent a new promising therapeutic target in the treatment of CRC

TRIM8: Making the Right Decision between the Oncogene and Tumour Suppressor Role

The TRIM8/GERP protein is a member of the TRIM family defined by the presence of a common domain structure composed of a tripartite motif including a RING-finger, one or two B-box domains, and a coiled-coil motif. The TRIM8 gene maps on chromosome 10 within a region frequently found deleted and rearranged in tumours and transcribes a 3.0-kB mRNA. Its expression is mostly ubiquitously in murine and human tissues, and in epithelial and lymphoid cells, it can be induced by IFNγ. The protein spans 551 aa and is highly conserved during evolution. TRIM8 plays divergent roles in many biological processes, including important functions in inflammation and cancer through regulating various signalling pathways. In regulating cell growth, TRIM8 exerts either a tumour suppressor action, playing a prominent role in regulating p53 tumour suppressor activity, or an oncogene function, through the positive regulation of the NF-κB pathway. The molecular mechanisms underlying this dual role in human cancer will be discussed in depth in this review, and it will highlight the challenge and importance of developing novel therapeutic strategies specifically aimed at blocking the pro-oncogenic arm of the TRIM8 signalling pathway without affecting its tumour suppressive effects