Structure and RNA binding of the third KH domain of poly(C)-binding protein 1

Poly(C)-binding proteins (CPs) are important regulators of mRNA stability and translational regulation. They recognize C-rich RNA through their triple KH (hn RNP K homology) domain structures and are thought to carry out their function though direct protection of mRNA sites as well as through interactions with other RNA-binding proteins. We report the crystallographically derived structure of the third domain of αCP1 to 2.1 Å resolution. αCP1-KH3 assumes a classical type I KH domain fold with a triple-stranded β-sheet held against a three-helix cluster in a βααββα configuration. Its binding affinity to an RNA sequence from the 3′-untranslated region (3′-UTR) of androgen receptor mRNA was determined using surface plasmon resonance, giving a K(d) of 4.37 μM, which is indicative of intermediate binding. A model of αCP1-KH3 with poly(C)-RNA was generated by homology to a recently reported RNA-bound KH domain structure and suggests the molecular basis for oligonucleotide binding and poly(C)-RNA specificity

A generalized no-broadcasting theorem

We prove a generalized version of the no-broadcasting theorem, applicable to essentially \emph{any} nonclassical finite-dimensional probabilistic model satisfying a no-signaling criterion, including ones with ``super-quantum'' correlations. A strengthened version of the quantum no-broadcasting theorem follows, and its proof is significantly simpler than existing proofs of the no-broadcasting theorem.Comment: 4 page

Three-dimensionality of space and the quantum bit: an information-theoretic approach

It is sometimes pointed out as a curiosity that the state space of quantum two-level systems, i.e. the qubit, and actual physical space are both three-dimensional and Euclidean. In this paper, we suggest an information-theoretic analysis of this relationship, by proving a particular mathematical result: suppose that physics takes place in d spatial dimensions, and that some events happen probabilistically (not assuming quantum theory in any way). Furthermore, suppose there are systems that carry "minimal amounts of direction information", interacting via some continuous reversible time evolution. We prove that this uniquely determines spatial dimension d=3 and quantum theory on two qubits (including entanglement and unitary time evolution), and that it allows observers to infer local spatial geometry from probability measurements.Comment: 13 + 22 pages, 9 figures. v4: some clarifications, in particular in Section V / Appendix C (added Example 39

The TRIM-NHL protein NHL-2 is a co-factor in the nuclear and somatic RNAi pathways in C. elegans

Proper regulation of germline gene expression is essential for fertility and maintaining species integrity. In the C. elegans germline, a diverse repertoire of regulatory pathways promote the expression of endogenous germline genes and limit the expression of deleterious transcripts to maintain genome homeostasis. Here we show that the conserved TRIM-NHL protein, NHL-2, plays an essential role in the C. elegans germline, modulating germline chromatin and meiotic chromosome organization. We uncover a role for NHL-2 as a co-factor in both positively (CSR-1) and negatively (HRDE-1) acting germline 22G-small RNA pathways and the somatic nuclear RNAi pathway. Furthermore, we demonstrate that NHL-2 is a bona fide RNA binding protein and, along with RNA-seq data point to a small RNA independent role for NHL-2 in regulating transcripts at the level of RNA stability. Collectively, our data implicate NHL-2 as an essential hub of gene regulatory activity in both the germline and soma

Grb7 SH2 domain structure and interactions with a cyclic peptide inhibitor of cancer cell migration and proliferation

<p>Abstract</p> <p>Background</p> <p>Human growth factor receptor bound protein 7 (Grb7) is an adapter protein that mediates the coupling of tyrosine kinases with their downstream signaling pathways. Grb7 is frequently overexpressed in invasive and metastatic human cancers and is implicated in cancer progression via its interaction with the ErbB2 receptor and focal adhesion kinase (FAK) that play critical roles in cell proliferation and migration. It is thus a prime target for the development of novel anti-cancer therapies. Recently, an inhibitory peptide (G7-18NATE) has been developed which binds specifically to the Grb7 SH2 domain and is able to attenuate cancer cell proliferation and migration in various cancer cell lines.</p> <p>Results</p> <p>As a first step towards understanding how Grb7 may be inhibited by G7-18NATE, we solved the crystal structure of the Grb7 SH2 domain to 2.1 Å resolution. We describe the details of the peptide binding site underlying target specificity, as well as the dimer interface of Grb 7 SH2. Dimer formation of Grb7 was determined to be in the μM range using analytical ultracentrifugation for both full-length Grb7 and the SH2 domain alone, suggesting the SH2 domain forms the basis of a physiological dimer. ITC measurements of the interaction of the G7-18NATE peptide with the Grb7 SH2 domain revealed that it binds with a binding affinity of K_d= ~35.7 μM and NMR spectroscopy titration experiments revealed that peptide binding causes perturbations to both the ligand binding surface of the Grb7 SH2 domain as well as to the dimer interface, suggesting that dimerisation of Grb7 is impacted on by peptide binding.</p> <p>Conclusion</p> <p>Together the data allow us to propose a model of the Grb7 SH2 domain/G7-18NATE interaction and to rationalize the basis for the observed binding specificity and affinity. We propose that the current study will assist with the development of second generation Grb7 SH2 domain inhibitors, potentially leading to novel inhibitors of cancer cell migration and invasion.</p

Social trajectories or disrupted identities? : Changing and competing models of teacher professionalism under New Labour

Since the 1988 Education Reform Act, the teacher’s role in England has changed in many ways, a process which intensified under New Labour after 1997. Conceptions of teacher professionalism have become more structured and formalized, often heavily influenced by government policy objectives. Career paths have become more diverse and specialised. In this article, three post-1997 professional roles are given consideration as examples of these new specialised career paths: Higher Level Teaching Assistants, Teach First trainees and Advanced Skills Teachers. The article goes on to examine such developments within teaching, using Bourdieu’s concept of habitus to inform the analysis, as well as Bernstein’s theories of knowledge and identity. The article concludes that there has been considerable specialization and subsequent fragmentation of roles within the teaching profession, as part of workforce remodelling initiatives. However, there is still further scope for developing a greater sense of professional cohesion through social activism initiatives, such as the children's agenda. This may produce more stable professional identities in the future as the role of teachers within the wider children’s workforce is clarified

Local randomness in Hardy's correlations: Implications from information causality principle

Study of nonlocal correlations in term of Hardy's argument has been quite popular in quantum mechanics. Recently Hardy's argument of non-locality has been studied in the context of generalized non-signaling theory as well as theory respecting information causality. Information causality condition significantly reduces the success probability for Hardy's argument when compared to the result based on non-signaling condition. Here motivated by the fact that maximally entangled state in quantum mechanics does not exhibit Hardy's non-local correlation, we do a qualitative study of the property of local randomness of measured observable on each side reproducing Hardy's non-locality correlation,in the context of information causality condition. On applying the necessary condition for respecting the principle of information causality, we find that there are severe restrictions on the local randomness of measured observable in contrast to results obtained from no-signaling condition.Still, there are some restrictions imposed by quantum mechanics that are not obtained from information causality condition.Comment: 6 pages, 2 tables, new references adde