Structure of a rare non-standard sequence k-turn bound by L7Ae protein

Kt-23 from Thelohania solenopsae is a rare RNA kink turn (k-turn) where an adenine replaces the normal guanine at the 2n position. L7Ae is a member of a strongly conserved family of proteins that bind a range of k-turn structures in the ribosome, box C/D and H/ACA small nucleolar RNAs and U4 small nuclear RNA. We have solved the crystal structure of T. solenopsae Kt-23 RNA bound to Archeoglobus fulgidus L7Ae protein at a resolution of 2.95 Å. The protein binds in the major groove displayed on the outer face of the k-turn, in a manner similar to complexes with standard k-turn structures. The k-turn adopts a standard N3 class conformation, with a single hydrogen bond from A2b N6 to A2n N3. This contrasts with the structure of the same sequence located in the SAM-I riboswitch, where it adopts an N1 structure, showing the inherent plasticity of k-turn structure. This potentially can affect any tertiary interactions in which the RNA participates

The k-junction motif in RNA structure

The k-junction is a structural motif in RNA comprising a three-way helical junction based upon kink turn (k-turn) architecture. A computer program written to examine relative helical orientation identified the three-way junction of the Arabidopsis TPP riboswitch as an elaborated k-turn. The Escherichia coli TPP riboswitch contains a related k-junction, and analysis of >11 000 sequences shows that the structure is common to these riboswitches. The k-junction exhibits all the key features of an N1-class k-turn, including the standard cross-strand hydrogen bonds. The third helix of the junction is coaxially aligned with the C (canonical) helix, while the k-turn loop forms the turn into the NC (non-canonical) helix. Analysis of ligand binding by ITC and global folding by gel electrophoresis demonstrates the importance of the k-turn nucleotides. Clearly the basic elements of k-turn structure are structurally well suited to generate a three-way helical junction, retaining all the key features and interactions of the k-turn

Hard x-ray polarimetry with the Ramaty High Energy Solar Spectroscopic Imager (RHESSI)

Although designed primarily as a hard X-ray imager and spectrometer, the Ramaty High Energy Solar Spectroscopic Imager (RHESSI) is also capable of measuring the polarization of hard X-rays (20-100 keV) from solar flares. This capability arises from the inclusion of a small unobstructed Be scattering element that is strategically located within the cryostat that houses the array of nine germanium detectors. The Ge detectors are segmented, with both a front and rear active volume. Low energy photons (below about 100 keV) can reach a rear segment of a Ge detector only indirectly, by scattering. Low energy photons from the Sun have a direct path to the Be and have a high probability of Compton scattering into a rear segment of a Ge detector. The azimuthal distribution of these scattered photons carries with it a signature of the linear polarization of the incident flux. Sensitivity estimates, based on simulations and in-flight background measurements, indicate that a 20-100 keV polarization sensitivity of less than a few percent can be achieved for X-class flares

Attenuation of hedgehog/GLI signaling by NT1721 extends survival in pancreatic cancer.

BackgroundPancreatic cancer is one of the most lethal malignancies due to frequent late diagnosis, aggressive tumor growth and metastasis formation. Continuously raising incidence rates of pancreatic cancer and a lack of significant improvement in survival rates over the past 30 years highlight the need for new therapeutic agents. Thus, new therapeutic agents and strategies are urgently needed to improve the outcome for patients with pancreatic cancer. Here, we evaluated the anti-tumor activity of a new natural product-based epidithiodiketopiperazine, NT1721, against pancreatic cancer.MethodsWe characterized the anticancer efficacy of NT1721 in multiple pancreatic cancer cell lines in vitro and in two orthotopic models. We also compared the effects of NT1721 to clinically used hedgehog inhibitors and the standard-of-care drug, gemcitabine. The effect of NT1721 on hedgehog/GLI signaling was assessed by determining the expression of GLI and GLI target genes both in vitro and in vivo.ResultsNT1721 displayed IC50 values in the submicromolar range in multiple pancreatic cancer cell lines, while largely sparing normal pancreatic epithelial cells. NT1721 attenuated hedgehog/GLI signaling through downregulation of GLI1/2 transcription factors and their downstream target genes, which reduced cell proliferation and invasion in vitro and significantly decreased tumor growth and liver metastasis in two preclinical orthotopic mouse models of pancreatic cancer. Importantly, treatment with NT1721 significantly improved survival times of mice with pancreatic cancer compared to the standard-of-care drug, gemcitabine.ConclusionsFavorable therapeutics properties, i.e. 10-fold lower IC50 values than clinically used hedgehog inhibitors (vismodegib, erismodegib), a 90% reduction in liver metastasis and significantly better survival times compared to the standard-of-care drug, gemcitabine, provide a rational for testing NT1721 in the clinic either as a single agent or possibly in combination with gemcitabine or other therapeutic agents in PDAC patients overexpressing GLI1/2. This could potentially result in promising new treatment options for patients suffering from this devastating disease

A note on the power divergence in lattice calculations of ΔI=1/2\Delta I = 1/2 K→ππK\to\pi\pi amplitudes at MK=MπM_{K}=M_{\pi}

In this note, we clarify a point concerning the power divergence in lattice calculations of $\Delta I = 1/2$ $K\to\pi\pi$ decay amplitudes. There have been worries that this divergence might show up in the Minkowski amplitudes at $M_{K}=M_{\pi}$ with all the mesons at rest. Here we demonstrate, via an explicit calculation in leading-order Chiral Perturbation Theory, that the power divergence is absent at the above kinematic point, as predicted by CPS symmetry.Comment: 5 pages, 2 figure