56 research outputs found
Tensor Decomposition Reveals Concurrent Evolutionary Convergences and Divergences and Correlations with Structural Motifs in Ribosomal RNA
Evolutionary relationships among organisms are commonly described by using a
hierarchy derived from comparisons of ribosomal RNA (rRNA) sequences. We propose that
even on the level of a single rRNA molecule, an organism's evolution is composed
of multiple pathways due to concurrent forces that act independently upon different
rRNA degrees of freedom. Relationships among organisms are then compositions of
coexisting pathway-dependent similarities and dissimilarities, which cannot be
described by a single hierarchy. We computationally test this hypothesis in
comparative analyses of 16S and 23S rRNA sequence alignments by using a tensor
decomposition, i.e., a framework for modeling composite data. Each alignment is
encoded in a cuboid, i.e., a third-order tensor, where nucleotides, positions and
organisms, each represent a degree of freedom. A tensor mode-1 higher-order singular
value decomposition (HOSVD) is formulated such that it separates each cuboid into
combinations of patterns of nucleotide frequency variation across organisms and
positions, i.e., “eigenpositions” and corresponding nucleotide-specific
segments of “eigenorganisms,” respectively, independent of a-priori
knowledge of the taxonomic groups or rRNA structures. We find, in support of our
hypothesis that, first, the significant eigenpositions reveal multiple similarities
and dissimilarities among the taxonomic groups. Second, the corresponding
eigenorganisms identify insertions or deletions of nucleotides exclusively conserved
within the corresponding groups, that map out entire substructures and are enriched
in adenosines, unpaired in the rRNA secondary structure, that participate in tertiary
structure interactions. This demonstrates that structural motifs involved in rRNA
folding and function are evolutionary degrees of freedom. Third, two previously
unknown coexisting subgenic relationships between Microsporidia and Archaea are
revealed in both the 16S and 23S rRNA alignments, a convergence and a divergence,
conferred by insertions and deletions of these motifs, which cannot be described by a
single hierarchy. This shows that mode-1 HOSVD modeling of rRNA alignments might be
used to computationally predict evolutionary mechanisms
Superior antitumoral activity of dimerized targeted single-chain TRAIL fusion proteins under retention of tumor selectivity
Although targeting of the death receptors (DRs) DR4 and DR5 still appears a suitable antitumoral strategy, the limited clinical responses to recombinant soluble TNF-related apoptosis inducing ligand (TRAIL) necessitate novel reagents with improved apoptotic activity/tumor selectivity. Apoptosis induction by a single-chain TRAIL (scTRAIL) molecule could be enhanced >10-fold by generation of epidermal growth factor receptor (EGFR)-specific scFv-scTRAIL fusion proteins. By forcing dimerization of scFv-scTRAIL based on scFv linker modification, we obtained a targeted scTRAIL composed predominantly of dimers (Db-scTRAIL), exceeding the activity of nontargeted scTRAIL ∼100-fold on Huh-7 hepatocellular and Colo205 colon carcinoma cells. Increased activity of Db-scTRAIL was also demonstrated on target-negative cells, suggesting that, in addition to targeting, oligomerization equivalent to an at least dimeric assembly of standard TRAIL per se enhances apoptosis signaling. In the presence of apoptosis sensitizers, such as the proteasomal inhibitor bortezomib, Db-scTRAIL was effective at picomolar concentrations in vitro (EC50 ∼2 × 10−12 M). Importantly, in vivo, Db-scTRAIL was well tolerated and displayed superior antitumoral activity in mouse xenograft (Colo205) tumor models. Our results show that both targeting and controlled dimerization of scTRAIL fusion proteins provides a strategy to enforce apoptosis induction, together with retained tumor selectivity and good in vivo tolerance
PReS-FINAL-2146: Trends in prescription of biologics and outcomes of juvenile idiopathic arthritis; results of the Dutch national arthritis and biologicals in children register
Transplantation and immunomodulatio
Competing jurisdictions: data privacy across the borders
Borderless cloud computing technologies are exacerbating tensions between European and other existing approaches to data privacy. On the one hand, in the European Union (EU), a series of data localisation initiatives are emerging with the objective of preserving Europe’s digital sovereignty, guaranteeing the respect of EU fundamental rights and preventing foreign law enforcement and intelligence agencies from accessing personal data. On the other hand, foreign countries are unilaterally adopting legislation requiring national corporations to disclose data stored in Europe, in this way bypassing jurisdictional boundaries grounded on physical data location. The chapter investigates this twofold dynamics by focusing particularly on the current friction between the EU data protection approach and the data privacy model of the United States (US) in the field of cloud computing
Structural Constraints Identified with Covariation Analysis in Ribosomal RNA
Covariation analysis is used to identify those positions with similar patterns of sequence variation in an alignment of RNA sequences. These constraints on the evolution of two positions are usually associated with a base pair in a helix. While mutual information (MI) has been used to accurately predict an RNA secondary structure and a few of its tertiary interactions, early studies revealed that phylogenetic event counting methods are more sensitive and provide extra confidence in the prediction of base pairs. We developed a novel and powerful phylogenetic events counting method (PEC) for quantifying positional covariation with the Gutell lab’s new RNA Comparative Analysis Database (rCAD). The PEC and MI-based methods each identify unique base pairs, and jointly identify many other base pairs. In total, both methods in combination with an N-best and helix-extension strategy identify the maximal number of base pairs. While covariation methods have effectively and accurately predicted RNAs secondary structure, only a few tertiary structure base pairs have been identified. Analysis presented herein and at the Gutell lab’s Comparative RNA Web (CRW) Site reveal that the majority of these latter base pairs do not covary with one another. However, covariation analysis does reveal a weaker although significant covariation between sets of nucleotides that are in proximity in the three-dimensional RNA structure. This reveals that covariation analysis identifies other types of structural constraints beyond the two nucleotides that form a base pair
Building a data sharing model for global genomic research.
Data sharing models designed to facilitate global business provide insights for improving transborder genomic data sharing. We argue that a flexible, externally endorsed, multilateral arrangement, combined with an objective third-party assurance mechanism, can effectively balance privacy with the need to share genomic data globally
Building a data sharing model for global genomic research
Data sharing models designed to facilitate global business provide insights for improving transborder genomic data sharing. We argue that a flexible, externally endorsed, multilateral arrangement, combined with an objective third-party assurance mechanism, can effectively balance privacy with the need to share genomic data globally
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