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Stitched α-Helical Peptides via Bis Ring-Closing Metathesis
Hilinski, Gerard J.,Kim, Young-Woo,Hong, Jooyeon,Kutchukian, Peter S.,Crenshaw, Charisse M.,Berkovitch, Shaunna S.,Chang, Andrew,Ham, Sihyun,Verdine, Gregory L. American Chemical Society 2014 JOURNAL OF THE AMERICAN CHEMICAL SOCIETY - Vol.136 No.35
<P>Conformationally stabilized α-helical peptides are capable of inhibiting disease-relevant intracellular or extracellular protein–protein interactions <I>in vivo</I>. We have previously reported that the employment of ring-closing metathesis to introduce a single all-hydrocarbon staple along one face of an α-helical peptide greatly increases α-helical content, binding affinity to a target protein, cell penetration through active transport, and resistance to proteolytic degradation. In an effort to improve upon this technology for stabilizing a peptide in a bioactive α-helical conformation, we report the discovery of an efficient and selective bis ring-closing metathesis reaction leading to peptides bearing multiple contiguous staples connected by a central spiro ring junction. Circular dichroism spectroscopy, NMR, and computational analyses have been used to investigate the conformation of these “stitched” peptides, which are shown to exhibit remarkable thermal stabilities. Likewise, trypsin proteolysis assays confirm the achievement of a structural rigidity unmatched by peptides bearing a single staple. Furthermore, fluorescence-activated cell sorting (FACS) and confocal microscopy assays demonstrate that stitched peptides display superior cell penetrating ability compared to their stapled counterparts, suggesting that this technology may be useful not only in the context of enhancing the drug-like properties of α-helical peptides but also in producing potent agents for the intracellular delivery of proteins and oligonucleotides.</P><P><B>Graphic Abstract</B> <IMG SRC='http://pubs.acs.org/appl/literatum/publisher/achs/journals/content/jacsat/2014/jacsat.2014.136.issue-35/ja505141j/production/images/medium/ja-2014-05141j_0007.gif'></P><P><A href='http://pubs.acs.org/doi/suppl/10.1021/ja505141j'>ACS Electronic Supporting Info</A></P>
( Yanhong Liu ),( Jeehwan Choe ),( Sheena Kim ),( Byeonghyeon Kim ),( Joy M. Campbell ),( Javier Polo ),( Joe D. Crenshaw ),( James E. Pettigrew ),( Minho Song ) 한국축산학회(구 한국동물자원과학회) 2018 한국축산학회지 Vol.60 No.6
Background: Stress causes inflammation that impairs intestinal barrier function. Dietary spray-dried plasma (SDP) has recognized anti-inflammatory effects and improvement of gut barrier function. Therefore, the purpose of this study was to investigate the effects of dietary SDP on intestinal morphology of mated female mice under stress condition. Results: Villus height, width, and area of small intestines were low on gestation day (GD) 3 or 4 under stress conditions, and higher later (Time, P < 0.05). Crypt depth of colon was low on GD 4 and higher later (Time, P < 0.05). Meanwhile, the SDP treatments improved (P < 0.05) intestinal morphology, indicated by increased villus height, villus width, villus area, and ratio between villus height and crypt depth of small intestines and crypt depth of colon, and by decreased crypt depth of small intestines, compared with the control diet. The SDP treatments also increased (P < 0.05) the number of goblet cells in intestines compared with the control diet. There were no differences between different levels of SDP. Conclusion: Dietary SDP improves intestinal morphology of mated female mice under stress condition.
Spray-dried plasma attenuates inflammation and improves pregnancy rate of mated female mice
Song, M.,Liu, Y.,Lee, J. J.,Che, T. M.,Soares-Almeida, J. A.,Chun, J. L.,Campbell, J. M.,Polo, J.,Crenshaw, J. D.,Seo, S. W.,Pettigrew, J. E. American Society of Animal Science 2015 Journal of Animal Science Vol. No.
<P>Three studies were conducted to test the hypothesis that dietary spray-dried plasma (SDP) might improve pregnancy rate by ameliorating inflammation, using mice in an experimental model that produces a low pregnancy rate. Mated female mice (C57BL/6 strain) were purchased and shipped from a vendor (Bar Harbor, ME) to the university facility (Urbana, IL) on the day the vaginal plug was found (gestation day [GD] 1), arriving at the laboratory on GD 3 after 2 d transport by air and ground. Mice (Exp. 1: <I>n</I> = 250, 16.0 ± 1.2 g BW; Exp. 2: <I>n</I> = 202, 16.2 ± 1.2 g BW; Exp. 3: <I>n</I> = 156, 16.4 ± 1.1 g BW) were housed in individual cages and randomly assigned to dietary treatments (Exp. 1: 0 [CON] and 8% SDP in the diet, ≥ 90 mice/diet; Exp. 2: 0, 1, 2, 4, and 8% SDP in the diet, ≥ 40 mice/diet; Exp. 3: 0, 1, and 8% SDP in the diet, 48 mice/diet) fed from arrival. In Exp. 1 and 2, pregnancy of each mouse was determined on GD 17 based on BW, shape of abdomen, and inspection postmortem, and maternal growth performance from GD 3 to 17 was measured. On GD 19, pregnant mice in Exp. 2 were euthanized to measure number of fetuses and fetal and placental weights. Pregnancy rates in CON were low in both Exp. 1 (11%) and Exp. 2 (7%). The SDP consistently and markedly increased (<I>P</I> < 0.05) pregnancy rates in both Exp. 1 (49%) and Exp. 2 (35–43%) compared with the CON. In Exp. 3, 12 randomly selected mice were euthanized immediately after they arrived as an initial group. From GD 4 to 7, randomly selected mice were also euthanized each day (12 mice/diet). After euthanasia, the abdominal cavity was opened to check pregnancy by uterine inspection and to collect blood and uterus samples for immune measurements. The SDP increased (<I>P</I> < 0.05; 40 vs. 15%) pregnancy rate compared with the CON. Concentrations of indicators of inflammation and stress (uterine TNF-α and IFN-γ, and serum TNF-α, C-reactive protein, and cortisol) were greatest (<I>P</I> < 0.05) and an anti-inflammatory cytokine (TGF-β1) was lowest (<I>P</I> < 0.05) soon after arrival, on GD 3 or 4. The SDP decreased (<I>P</I> < 0.05) the uterine concentrations of TNF-α and IFN-γ, and serum TNF-α, C-reactive protein, and cortisol, compared with the CON, but increased (<I>P</I> < 0.05) the uterine concentration of TGF-β1. In conclusion, dietary SDP improves the low pregnancy rates in this model, apparently by attenuating inflammation.</P>
Goad, M. R.,Korista, K. T.,Rosa, G. De,Kriss, G. A.,Edelson, R.,Barth, A. J.,Ferland, G. J.,Kochanek, C. S.,Netzer, H.,Peterson, B. M.,Bentz, M. C.,Bisogni, S.,Crenshaw, D. M.,Denney, K. D.,Ely, J.,Fa American Astronomical Society 2016 The Astrophysical journal Vol.824 No.1
<P>During an intensive Hubble Space Telescope (HST) Cosmic Origins Spectrograph (COS) UV monitoring campaign of the Seyfert 1 galaxy NGC 5548 performed from 2014 February to July, the normally highly correlated far UV continuum and broad emission line variations decorrelated for similar to 60-70 days, starting similar to 75 days after the first HST/COS observation. Following this anomalous state, the flux and variability of the broad emission lines returned to a more normal state. This transient behavior, characterized by significant deficits in flux and equivalent width of the strong broad UV emission lines, is the first of its kind to be unambiguously identified in an active galactic nucleus reverberation mapping campaign. The largest corresponding emission line flux deficits occurred for the high ionization, collisionally excited lines C IV and Si IV(+O IV]), and also He II(+O III]), while the anomaly in Ly alpha was substantially smaller. This pattern of behavior indicates a depletion in the flux of photons with E-ph > 54 eV relative to those near 13.6 eV. We suggest two plausible mechanisms for the observed behavior: (i) temporary obscuration of the ionizing continuum incident upon broad line region (BLR) clouds by a moving veil of material lying between the inner accretion disk and inner (BLR), perhaps resulting from an episodic ejection of material from the disk, or (ii) a temporary change in the intrinsic ionizing continuum spectral energy distribution resulting in a deficit of ionizing photons with energies > 54 eV, possibly due to a transient restructuring of the Comptonizing atmosphere above the disk. Current evidence appears to favor the latter explanation.</P>