Structure-Based Design, Synthesis and Bioactivity of a New Anti-TNFα Cyclopeptide

As opposed to small molecules, macrocyclic peptides possess a large surface area and are recognised as promising candidates to selectively treat diseases by disrupting specific protein–protein interactions (PPIs). Due to the difficulty in predicting cyclopeptide conformations in solution, the de novo design of bioactive cyclopeptides remains significantly challenging. In this study, we used the combination of conformational analyses and molecular docking studies to design a new cyclopeptide inhibitor of the interaction between the human tumour necrosis factor alpha (TNFα) and its receptor TNFR-1. This interaction is a key in mediating the inflammatory response to tissue injury and infection in humans, and it is also an important causative factor of rheumatoid arthritis, psoriasis and inflammatory bowel disease. The solution state NMR structure of the cyclopeptide was determined, which helped to deduce its mode of interaction with TNFα. TNFα sensor cells were used to evaluate the biological activity of the peptide

Mirrored one-nucleon knockout reactions to the T-z = +/- 3/2 A=53 mirror nuclei

Background: The study of excited states in mirror nuclei allows us to extract information on charge-dependent (i.e., isospin-nonconserving) interactions in nuclei. Purpose: To extend previous studies of mirror nuclei in the f72 region, investigating charge symmetry breaking of the strong nuclear force. Methods: γ-ray spectroscopy has been performed for the mirror (Tz=±32) pair Ni53 and Mn53, produced via mirrored one-nucleon knockout reactions. Results: Several new transitions have been identified in Ni53 from which a new level scheme has been constructed. Cross sections for knockout have been analyzed and compared with reaction model calculations where evidence is found for knockout from high-spin isomeric states. Mirror energy differences between isobaric analog states have been computed, compared to large scale shell-model calculations, and interpreted in terms of isospin-nonconserving effects. In addition, lifetimes for the long-lived Jπ=52−1 analog states in both Mn53 and Ni53 have been extracted through lineshape analysis, giving half-lives of t12=120(14) ps and t12=198(12) ps, respectively. Conclusions: The inclusion of a set of isovector isospin-nonconserving matrix elements to the shell-model calculations gave the best agreement with the experimental data

Derivation and Characterization of Induced Pluripotent Stem Cells from Equine Fibroblasts

Pluripotent stem cells offer unprecedented potential not only for human medicine but also for veterinary medicine, particularly in relation to the horse. Induced pluripotent stem cells (iPSCs) are particularly promising, as they are functionally similar to embryonic stem cells and can be generated in vitro in a patient-specific manner. In this study, we report the generation of equine iPSCs from skin fibroblasts obtained from a foal and reprogrammed using viral vectors coding for murine Oct4, Sox2, c-Myc, and Klf4 sequences. The reprogrammed cell lines were morphologically similar to iPSCs reported from other species and could be stably maintained over more than 30 passages. Immunostaining and polymerase chain reaction analyses revealed that these cell lines expressed an array of endogenous markers associated with pluripotency, including OCT4, SOX2, NANOG, REX1, LIN28, SSEA1, SSEA4, and TRA1-60. Furthermore, under the appropriate conditions, the equine iPSCs readily formed embryoid bodies and differentiated in vitro into cells expressing markers of ectoderm, mesoderm, and endoderm, and when injected into immunodeficient mice, gave raise to tumors containing differentiated derivatives of the 3 germ layers. Finally, we also reprogrammed fibroblasts from a 2-year-old horse. The reprogrammed cells were similar to iPSCs derived from neonatal fibroblasts in terms of morphology, expression of pluripotency markers, and differentiation ability. The generation of these novel cell lines constitutes an important step toward the understanding of pluripotency in the horse, and paves the way for iPSC technology to potentially become a powerful research and clinical tool in veterinary biomedicine

The Peculiar SN 2005hk: Do Some Type Ia Supernovae Explode as Deflagrations?

We present extensive u'g'r'i'BVRIYJHKs photometry and optical spectroscopy of SN 2005hk. These data reveal that SN 2005hk was nearly identical in its observed properties to SN 2002cx, which has been called ``the most peculiar known type Ia supernova.'' Both supernovae exhibited high ionization SN 1991T-like pre-maximum spectra, yet low peak luminosities like SN 1991bg. The spectra reveal that SN 2005hk, like SN 2002cx, exhibited expansion velocities that were roughly half those of typical type Ia supernovae. The R and I light curves of both supernovae were also peculiar in not displaying the secondary maximum observed for normal type Ia supernovae. Our YJH photometry of SN 2005hk reveals the same peculiarity in the near-infrared. By combining our optical and near-infrared photometry of SN 2005hk with published ultraviolet light curves obtained with the Swift satellite, we are able to construct a bolometric light curve from ~10 days before to ~60 days after B maximum. The shape and unusually low peak luminosity of this light curve, plus the low expansion velocities and absence of a secondary maximum at red and near-infrared wavelengths, are all in reasonable agreement with model calculations of a 3D deflagration which produces ~0.25 M_sun of 56Ni.Comment: Accepted by PASP, to appear in April 2007 issue, 63 pages, 16 figures, 11 table

Mirrored one-nucleon knockout reactions to the Tz=± 32 A=53 mirror nuclei

Background: The study of excited states in mirror nuclei allows us to extract information on charge-dependent (i.e., isospin-nonconserving) interactions in nuclei. Purpose: To extend previous studies of mirror nuclei in the f72 region, investigating charge symmetry breaking of the strong nuclear force. Methods: γ-ray spectroscopy has been performed for the mirror (Tz=±32) pair Ni53 and Mn53, produced via mirrored one-nucleon knockout reactions. Results: Several new transitions have been identified in Ni53 from which a new level scheme has been constructed. Cross sections for knockout have been analyzed and compared with reaction model calculations where evidence is found for knockout from high-spin isomeric states. Mirror energy differences between isobaric analog states have been computed, compared to large scale shell-model calculations, and interpreted in terms of isospin-nonconserving effects. In addition, lifetimes for the long-lived Jπ=521- analog states in both Mn53 and Ni53 have been extracted through lineshape analysis, giving half-lives of t12=120(14) ps and t12=198(12) ps, respectively. Conclusions: The inclusion of a set of isovector isospin-nonconserving matrix elements to the shell-model calculations gave the best agreement with the experimental data

Different molecular conformations in the crystal structures of three 5-nitroimidazolyl derivatives

Acknowledgements We thank the EPSRC National Crystallography Service (University of Southampton) for the X-ray data collections.Peer reviewedPublisher PD

Placental vascularity and markers of angiogenesis in relation to prenatal growth status in overnourished adolescent ewes.

INTRODUCTION: Placental vascularity may be important in the development of fetal growth restriction (FGR). The overnourished adolescent ewe is a robust model of the condition, with ∼50% of offspring demonstrating FGR (birthweight >2 standard deviations below optimally-fed control mean). We studied whether placental vascularity, angiogenesis and glucose transport reflect FGR severity. METHODS: Singleton pregnancies were established in adolescent ewes either overnourished to putatively restrict fetoplacental growth (n = 27) or control-fed (n = 12). At 131d (term = 145d) pregnancies were interrupted and fetuses classified as FGR (n = 17,  Non-FGR > FGR and fetal:placental weight ratios were higher in overnourished versus Control groups. COT vascular indices were Non-FGR > FGR > Control. COT-CAD, CSD and APC were significantly greater in Non-FGR overnourished versus Control and intermediate in FGR groups. CAR vascularity did not differ. CAR-VEGFA/FLT1/KDR/ANGPT1/ANGPT2/SLC2A1/SLC2A3 mRNA was lower and COT-ANGPT2 higher in overnourished versus Control groups. DISCUSSION: Relative to control-intake pregnancy, overnourished pregnancies are characterised by higher COT vascularity, potentially a compensatory response to reduced nutrient supply, reflected by higher fetal:placental weight ratios. Compared with overnourished pregnancies where fetal growth is relatively preserved, overnourished pregnancies culminating in marked FGR have less placental vascularity, suggesting incomplete adaptation to the prenatal insult