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MYC is the most altered oncogene in human cancer, and belongs to a large family of genes, including MYCN and MYCL. Recently, while assessing the degree of correlation between MYC gene rearrangement and MYC protein expression in aggressive B-cell lymphomas, we observed few Burkitt lymphoma (BL) cases lacking MYC protein expression despite the translocation involving the MYC gene. Therefore, in the present study we aimed to better characterize such cases. Our results identified two sub-groups of MYC protein negative BL: one lacking detectable MYC protein expression but presenting MYCN mRNA and protein expression; the second characterized by the lack of both MYC and MYCN proteins but showing MYC mRNA. Interestingly, the two sub-groups presented a different pattern of SNVs affecting MYC gene family members that may induce the switch from MYC to MYCN. Particulary, MYCN-expressing cases show MYCN SNVs at interaction interface that stabilize the protein associated with loss-of-function of MYC. This finding highlights MYCN as a reliable diagnostic marker in such cases. Nevertheless, due to the overlapping clinic, morphology and immunohistochemistry (apart for MYC versus MYCN protein expression) of both sub-groups, the described cases represent bona fide BL according to the current criteria of the World Health Organization. [ABSTRACT FROM AUTHOR]

Background: Mutations in ATP-transporters ATPB81, ABCB11, and ABCB4 are responsible for progressive familial intrahepatic cholestasis (PFIC) 1, 2 and 3, and recently the gene for tight junction protein-2 (TJP2) has been linked to PFIC4.Aim: As these four genes have been poorly studied in young people and adults, we investigated them in this context here.Methods: In patients with cryptogenic cholestasis, we analyzed the presence of mutations by high-throughput sequencing. Bioinformatics analyses were performed for mechanistic and functional predictions of their consequences on biomolecular interaction interfaces.Results: Of 108 patients, 48 whose cause of cholestasis was not established were submitted to molecular analysis. Pathogenic/likely pathogenic mutations were found in ten (21%) probands for 13 mutations: two in ATP8B 1, six in ABCB11, two in ABCB4, three in TJP2. We also identified seven variants of uncertain significance: two in ATP8B1, one in ABCB11, two in ABCB4 and two in TJP2. Finally, we identified 11 benign/likely benign variants. Patients with pathogenic/likely pathogenic mutations had higher levels of liver stiffness (measured by FibroScan®) and bile acids, as well as higher rates of cholestatic histological features, compared to the patients without at least likely pathogenic mutations. The multivariate analysis showed that itching was the only independent factor associated with disease-causing mutations (OR 5.801, 95% CI 1.244-27.060, p = 0.025).Conclusions: Mutations in the genes responsible for PFIC may be involved in both young and adults with cryptogenic cholestasis in a considerable number of cases, including in heterozygous status. Diagnosis should always be suspected, particularly in the presence of itching. [ABSTRACT FROM AUTHOR]

A paramount task in RNA interference research is to decipher the complex biology of cellular effectors, exemplified in humans by four pleiotropic Argonaute proteins (Ago1-Ago4). Here, we exploited DNA family shuffling, a molecular evolution technology, to generate chimeric Ago protein libraries for dissection of intricate phenotypes independently of prior structural knowledge. Through shuffling of human Ago2 and Ago3, we discovered two N-terminal motifs that govern RNA cleavage in concert with the PIWI domain. Structural modeling predicts an impact on protein rigidity and/or RNA-PIWI alignment, suggesting new mechanistic explanations for Ago3's slicing deficiency. Characterization of hybrids including Ago1 and Ago4 solidifies that slicing requires the juxtaposition and combined action of multiple disseminated modules. We also present a Gateway library of codon-optimized chimeras of human Ago1-Ago4 and molecular evolution analysis software as resources for future investigations into RNA interference sequence-structure-function relationships. [ABSTRACT FROM AUTHOR]

Burkitt lymphoma is a mature aggressive B-cell lymphoma derived from germinal center B cells. Its cytogenetic hallmark is the Burkitt translocation t(8;14)(q24;q32) and its variants, which juxtapose the MYC oncogene with one of the three immunoglobulin loci. Consequently, MYC is deregulated, resulting in massive perturbation of gene expression. Nevertheless, MYC deregulation alone seems not to be sufficient to drive Burkitt lymphomagenesis. By whole-genome, whole-exome and transcriptome sequencing of four prototypical Burkitt lymphomas with immunoglobulin gene (IG)-MYC translocation, we identified seven recurrently mutated genes. One of these genes, ID3, mapped to a region of focal homozygous loss in Burkitt lymphoma. In an extended cohort, 36 of 53 molecularly defined Burkitt lymphomas (68%) carried potentially damaging mutations of ID3. These were strongly enriched at somatic hypermutation motifs. Only 6 of 47 other B-cell lymphomas with the IG-MYC translocation (13%) carried ID3 mutations. These findings suggest that cooperation between ID3 inactivation and IG-MYC translocation is a hallmark of Burkitt lymphomagenesis. [ABSTRACT FROM AUTHOR]

Biological interaction networks have been in the scientific limelight for nearly a decade. Increasingly, the concept of network biology and its various applications are becoming more commonplace in the community. Recent years have seen networks move from pretty pictures with limited application to solid concepts that are increasingly used to understand the fundamentals of biology. They are no longer merely results of postgenome analysis projects, but are now the starting point of many of the most exciting new scientific developments. We discuss here recent progress in identifying and understanding interaction networks, new tools that use them in predictive ways in exciting areas of biology, and how they have become the focus of many efforts to study, design and tinker with biological systems, with applications in biomedicine, bioengineering, ecology and beyond. [ABSTRACT FROM AUTHOR]

Much of systems biology aims to predict the behaviour of biological systems on the basis of the set of molecules involved. Understanding the interactions between these molecules is therefore crucial to such efforts. Although many thousands of interactions are known, precise molecular details are available for only a tiny fraction of them. The difficulties that are involved in experimentally determining atomic structures for interacting proteins make predictive methods essential for progress. Structural details can ultimately turn abstract system representations into models that more accurately reflect biological reality. [ABSTRACT FROM AUTHOR]

Previous studies have suggested that nature is restricted to about 1,000 protein folds to perform a great diversity of functions. Here, we use protein interaction data from different sources and three-dimensional structures to suggest that the total number of interaction types is also limited, and estimate that most interactions in nature will conform to one of about 10,000 types. We currently know fewer than 2,000, and at the present rate of structure determination, it will be more than 20 years before we know a full representative set. [ABSTRACT FROM AUTHOR]

Discusses the roles for structure in biology and drug discovery. Role played by bioinformatics in structural genomics; Major issue for proponents of structural genomics; Benefits of a successful structural genomics effort.

Burkitt lymphoma (BL) is the most common B-cell lymphoma in children. Within the International Cancer Genome Consortium (ICGC), we performed whole genome and transcriptome sequencing of 39 sporadic BL. Here, we unravel interaction of structural, mutational, and transcriptional changes, which contribute to MYC oncogene dysregulation together with the pathognomonic IG-MYC translocation. Moreover, by mapping IGH translocation breakpoints, we provide evidence that the precursor of at least a subset of BL is a B-cell poised to express IGHA. We describe the landscape of mutations, structural variants, and mutational processes, and identified a series of driver genes in the pathogenesis of BL, which can be targeted by various mechanisms, including IG-non MYC translocations, germline and somatic mutations, fusion transcripts, and alternative splicing. Burkitt lymphoma (BL) is the most common pediatric B-cell lymphoma. Here, within the International Cancer Genome Consortium, the authors performed whole genome and transcriptome sequencing of 39 sporadic BL, describing the landscape of mutations, structural variants, and mutational processes that underpin this disease how alterations on different cellular levels cooperate in deregulating key pathways and complexes. [ABSTRACT FROM AUTHOR]

The article presents the authors' insights regarding the study of Y. Zhang and colleagues on the metabolic reconstruction of Thermotoga maritima. It states that the researchers use the structural information in identifying substrates in the metabolic network and in testing the patchwork theory and retrograde model. Furthermore, it notes that the researchers were able to study evolution using the radical combinations of datasets on metabolomics, structural biology, and systems simulation.

The article discusses the role of short peptide segments in human platelets aggregation. A computational approach to discover linear peptides sequences is discussed. The article mentions the discovery of directed in silico screen for identifying candidate peptides from the 3000 proteins expressed in platelets. The article concludes that this discovery will lead to new therapies for various diseases such as cardiovascular disease.