tRNA Anticodon Cleavage by Target-Activated CRISPR-Cas13a Effector

Type VI CRISPR-Cas systems are among the few CRISPR varieties that target exclusively RNA. The CRISPR RNA–guided, sequence-specific binding of target RNAs, such as phage transcripts, activates the type VI effector, Cas13. Once activated, Cas13 causes collateral RNA cleavage, which induces bacterial cell dormancy, thus protecting the host population from the phage spread. We show here that the principal form of collateral RNA degradation elicited by Leptotrichia shahii Cas13a expressed in Escherichia coli cells is the cleavage of anticodons in a subset of transfer RNAs (tRNAs) with uridine-rich anticodons. This tRNA cleavage is accompanied by inhibition of protein synthesis, thus providing defense from the phages. In addition, Cas13a-mediated tRNA cleavage indirectly activates the RNases of bacterial toxin-antitoxin modules cleaving messenger RNA, which could provide a backup defense. The mechanism of Cas13a-induced antiphage defense resembles that of bacterial anticodon nucleases, which is compatible with the hypothesis that type VI effectors evolved from an abortive infection module encompassing an anticodon nuclease

Network analysis of human glaucomatous optic nerve head astrocytes

<p>Abstract</p> <p>Background</p> <p>Astrocyte activation is a characteristic response to injury in the central nervous system, and can be either neurotoxic or neuroprotective, while the regulation of both roles remains elusive.</p> <p>Methods</p> <p>To decipher the regulatory elements controlling astrocyte-mediated neurotoxicity in glaucoma, we conducted a systems-level functional analysis of gene expression, proteomic and genetic data associated with reactive optic nerve head astrocytes (ONHAs).</p> <p>Results</p> <p>Our reconstruction of the molecular interactions affected by glaucoma revealed multi-domain biological networks controlling activation of ONHAs at the level of intercellular stimuli, intracellular signaling and core effectors. The analysis revealed that synergistic action of the transcription factors AP-1, vitamin D receptor and Nuclear Factor-kappaB in cross-activation of multiple pathways, including inflammatory cytokines, complement, clusterin, ephrins, and multiple metabolic pathways. We found that the products of over two thirds of genes linked to glaucoma by genetic analysis can be functionally interconnected into one epistatic network via experimentally-validated interactions. Finally, we built and analyzed an integrative disease pathology network from a combined set of genes revealed in genetic studies, genes differentially expressed in glaucoma and closely connected genes/proteins in the interactome.</p> <p>Conclusion</p> <p>Our results suggest several key biological network modules that are involved in regulating neurotoxicity of reactive astrocytes in glaucoma, and comprise potential targets for cell-based therapy.</p

Molecular Characteristics of the Mycobacterium tuberculosis LAM-RUS Family Prevalent in Central Russia▿ †

We analyzed IS6110-associated polymorphisms in the phospholipase C genes of 107 isolates of Mycobacterium tuberculosis selected to be representative of isolates circulating in central Russia. We found that the majority of Latin American-Mediterranean family strains contained an insertion in a unique position in the plcA gene, suggesting a common ancestor. This insertion can serve as a specific genetic marker for this group, which we designate the LAM-RUS family

Bimodal gene expression patterns in breast cancer

We identified a set of genes with an unexpected bimodal distribution among breast cancer patients in multiple studies. The property of bimodality seems to be common, as these genes were found on multiple microarray platforms and in studies with different end-points and patient cohorts. Bimodal genes tend to cluster into small groups of four to six genes with synchronised expression within the group (but not between the groups), which makes them good candidates for robust conditional descriptors. The groups tend to form concise network modules underlying their function in cancerogenesis of breast neoplasms

Representations of rational Cherednik algebras with minimal support and torus knots

In this paper we obtain several results about representations of rational Cherednik algebras, and discuss their applications. Our first result is the Cohen-Macaulayness property (as modules over the polynomial ring) of Cherednik algebra modules with minimal support. Our second result is an explicit formula for the character of an irreducible minimal support module in type An-1 for c=mn, and an expression of its quasispherical part (i.e., the isotypic part of "hooks") in terms of the HOMFLY polynomial of a torus knot colored by a Young diagram. We use this formula and the work of Calaque, Enriquez and Etingof to give explicit formulas for the characters of the irreducible equivariant D-modules on the nilpotent cone for SLm. Our third result is the construction of the Koszul-BGG complex for the rational Cherednik algebra, which generalizes the construction of the Koszul-BGG resolution from [3] and [21], and the calculation of its homology in type A. We also show in type A that the differentials in the Koszul-BGG complex are uniquely determined by the condition that they are nonzero homomorphisms of modules over the Cherednik algebra. Finally, our fourth result is the symmetry theorem, which identifies the quasispherical components in the representations with minimal support over the rational Cherednik algebras Hmn(Sn) and Hnm(Sm). In fact, we show that the simple quotients of the corresponding quasispherical subalgebras are isomorphic as filtered algebras. This symmetry was essentially established in [8] in the spherical case, and in [24] in the case GCD(m, n)=1, and it has a natural interpretation in terms of invariants of torus knots