Synthesis of triazole-linked morpholino oligonucleotides via Cu1 catalysed cycloaddition

Triazole-linked morpholino (TLMO) oligonucleic acids were synthesised using the CuI catalysed (3 + 2) azide–alkyne cycloaddition (CuAAC) reaction. The modified DNA analogues were incorporated into 13-mer sequences via solid phase synthesis. UV melting experiments showed that the TLMO modification gives higher Tm values than the corresponding TLDNA modification

Genome aliquoting with double cut and join

<p>Abstract</p> <p>Background</p> <p>The <it>genome aliquoting probem </it>is, given an observed genome <it>A </it>with <it>n </it>copies of each gene, presumed to descend from an <it>n</it>-way polyploidization event from an ordinary diploid genome <it>B</it>, followed by a history of chromosomal rearrangements, to reconstruct the identity of the original genome <it>B'</it>. The idea is to construct <it>B'</it>, containing exactly one copy of each gene, so as to minimize the number of rearrangements <it>d</it>(<it>A, B' </it>⊕ <it>B' </it>⊕ ... ⊕ <it>B'</it>) necessary to convert the observed genome <it>B' </it>⊕ <it>B' </it>⊕ ... ⊕ <it>B' </it>into <it>A</it>.</p> <p>Results</p> <p>In this paper we make the first attempt to define and solve the genome aliquoting problem. We present a heuristic algorithm for the problem as well the data from our experiments demonstrating its validity.</p> <p>Conclusion</p> <p>The heuristic performs well, consistently giving a non-trivial result. The question as to the existence or non-existence of an exact solution to this problem remains open.</p

The Extreme Small Scales: Do Satellite Galaxies Trace Dark Matter?

We investigate the radial distribution of galaxies within their host dark matter halos by modeling their small-scale clustering, as measured in the Sloan Digital Sky Survey. Specifically, we model the Jiang et al. (2011) measurements of the galaxy two-point correlation function down to very small projected separations (10 < r < 400 kpc/h), in a wide range of luminosity threshold samples (absolute r-band magnitudes of -18 up to -23). We use a halo occupation distribution (HOD) framework with free parameters that specify both the number and spatial distribution of galaxies within their host dark matter halos. We assume that the first galaxy in each halo lives at the halo center and that additional satellite galaxies follow a radial density profile similar to the dark matter Navarro-Frenk-White (NFW) profile, except that the concentration and inner slope are allowed to vary. We find that in low luminosity samples, satellite galaxies have radial profiles that are consistent with NFW. M_r < -20 and brighter satellite galaxies have radial profiles with significantly steeper inner slopes than NFW (we find inner logarithmic slopes ranging from -1.6 to -2.1, as opposed to -1 for NFW). We define a useful metric of concentration, M_(1/10), which is the fraction of satellite galaxies (or mass) that are enclosed within one tenth of the virial radius of a halo. We find that M_(1/10) for low luminosity satellite galaxies agrees with NFW, whereas for luminous galaxies it is 2.5-4 times higher, demonstrating that these galaxies are substantially more centrally concentrated within their dark matter halos than the dark matter itself. Our results therefore suggest that the processes that govern the spatial distribution of galaxies, once they have merged into larger halos, must be luminosity dependent, such that luminous galaxies become poor tracers of the underlying dark matter.Comment: 12 pages, 6 figures, Accepted to Ap

ADAM10 is essential for Notch2-dependent marginal zone B cell development and CD23 cleavage in vivo

The proteolytic activity of a disintegrin and metalloproteinase 10 (ADAM10) regulates cell-fate decisions in Drosophila and mouse embryos. However, in utero lethality of ADAM10−/− mice has prevented examination of ADAM10 cleavage events in lymphocytes. To investigate their role in B cell development, we generated B cell–specific ADAM10 knockout mice. Intriguingly, deletion of ADAM10 prevented development of the entire marginal zone B cell (MZB) lineage. Additionally, cleavage of the low affinity IgE receptor, CD23, was profoundly impaired, but subsequent experiments demonstrated that ADAM10 regulates CD23 cleavage and MZB development by independent mechanisms. Development of MZBs is dependent on Notch2 signaling, which requires proteolysis of the Notch2 receptor by a previously unidentified proteinase. Further experiments revealed that Notch2 signaling is severely impaired in ADAM10-null B cells. Thus, ADAM10 critically regulates MZB development by initiating Notch2 signaling. This study identifies ADAM10 as the in vivo CD23 sheddase and an important regulator of B cell development. Moreover, it has important implications for the treatment of numerous CD23- and Notch-mediated pathologies, ranging from allergy to cancer

BCX4430 – A broad-spectrum antiviral adenosine nucleoside analog under development for the treatment of Ebola virus disease

SummaryThe adenosine nucleoside analog BCX4430 is a direct-acting antiviral drug under investigation for the treatment of serious and life-threatening infections from highly pathogenic viruses, such as the Ebola virus. Cellular kinases phosphorylate BCX4430 to a triphosphate that mimics ATP; viral RNA polymerases incorporate the drug's monophosphate nucleotide into the growing RNA chain, causing premature chain termination. BCX4430 is active in vitro against many RNA viral pathogens, including the filoviruses and emerging infectious agents such as MERS-CoV and SARS-CoV. In vivo, BCX4430 is active after intramuscular, intraperitoneal, and oral administration in a variety of experimental infections. In nonclinical studies involving lethal infections with Ebola virus, Marburg virus, Rift Valley fever virus, and Yellow Fever virus, BCX4430 has demonstrated pronounced efficacy. In experiments conducted in several models, both a reduction in the viral load and an improvement in survival were found to be related to the dose of BCX4430. A Phase 1 clinical trial of intramuscular administration of BCX4430 in healthy subjects is currently ongoing

Sorting by reversals, block interchanges, tandem duplications, and deletions

<p>Abstract</p> <p>Background</p> <p>Finding sequences of evolutionary operations that transform one genome into another is a classic problem in comparative genomics. While most of the genome rearrangement algorithms assume that there is exactly one copy of each gene in both genomes, this does not reflect the biological reality very well – most of the studied genomes contain duplicated gene content, which has to be removed before applying those algorithms. However, dealing with unequal gene content is a very challenging task, and only few algorithms allow operations like duplications and deletions. Almost all of these algorithms restrict these operations to have a fixed size.</p> <p>Results</p> <p>In this paper, we present a heuristic algorithm to sort an ancestral genome (with unique gene content) into a genome of a descendant (with arbitrary gene content) by reversals, block interchanges, tandem duplications, and deletions, where tandem duplications and deletions are of arbitrary size.</p> <p>Conclusion</p> <p>Experimental results show that our algorithm finds sorting sequences that are close to an optimal sorting sequence when the ancestor and the descendant are closely related. The quality of the results decreases when the genomes get more diverged or the genome size increases. Nevertheless, the calculated distances give a good approximation of the true evolutionary distances.</p

Pathological Investigation of Congenital Bicuspid Aortic Valve Stenosis, Compared with Atherosclerotic Tricuspid Aortic Valve Stenosis and Congenital Bicuspid Aortic Valve Regurgitation

Congenital bicuspid aortic valve (CBAV) is the main cause of aortic stenosis (AS) in young adults. However, the histopathological features of AS in patients with CBAV have not been fully investigated.We examined specimens of aortic valve leaflets obtained from patients who had undergone aortic valve re/placement at our institution for severe AS with CBAV (n = 24, CBAV-AS group), severe AS with tricuspid aortic valve (n = 24, TAV-AS group), and severe aortic regurgitation (AR) with CBAV (n = 24, CBAV-AR group). We compared the histopathological features among the three groups. Pathological features were classified using semi-quantitative methods (graded on a scale 0 to 3) by experienced pathologists without knowledge of the patients' backgrounds. The severity of inflammation, neovascularization, and calcium and cholesterol deposition did not differ between the CBAV-AS and TAV-AS groups, and these four parameters were less marked in the CBAV-AR group than in the CBAV-AS (all p<0.01). Meanwhile, the grade of valvular fibrosis was greater in the CBAV-AS group, compared with the TAV-AS and CBAV-AR groups (both p<0.01). In AS patients, thickness of fibrotic lesions was greater on the aortic side than on the ventricular side (both p<0.01). Meanwhile, thickness of fibrotic lesions was comparable between the aortic and ventricular sides in CBAV-AR patients (p = 0.35).Valvular fibrosis, especially on the aortic side, was greater in patients with CBAV-AS than in those without, suggesting a difference in the pathogenesis of AS between CBAV and TAV

In situ single-crystal X-ray diffraction studies of physisorption and chemisorption of SO2 within a metal-organic framework and its competitive adsorption with water

Funding: The authors are also grateful for financial assistancefrom the ERC under advanced grant 787073, the EPSRC for a studentship (EP/N509759/1) and support via the Collaborative Computational Projecton NMR Crystallography CCP-NC (EP/T02662/1), and the CRITICAT Centre for Doctoral Training (EP/L016419/1).Living on an increasingly polluted planet, the removal of toxic pollutants such as sulfur dioxide (SO2) from the troposphere and power station flue gas is becoming more and more important. The CPO-27/MOF-74 family of metal–organic frameworks (MOFs) with their high densities of open metal sites is well suited for the selective adsorption of gases that, like SO2, bind well to metals and have been extensively researched both practically and through computer simulations. However, until now, focus has centered upon the binding of SO2 to the open metal sites in this MOF (called chemisorption, where the adsorbent–adsorbate interaction is through a chemical bond). The possibility of physisorption (where the adsorbent–adsorbate interaction is only through weak intermolecular forces) has not been identified experimentally. This work presents an in situ single-crystal X-ray diffraction (scXRD) study that identifies discrete adsorption sites within Ni-MOF-74/Ni-CPO-27, where SO2 is both chemisorbed and physisorbed while also probing competitive adsorption of SO2 of these sites when water is present. Further features of this site have been confirmed by variable SO2 pressure scXRD studies, DFT calculations, and IR studies.Publisher PDFPeer reviewe