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Chiricozzi A, Saraceno R, Chimenti MS, Guttman-Yassky E, Krueger JG
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Role of IL-23 in the pathogenesis of psoriasis: a novel potential therapeutic target?
EXPERT OPINION ON THERAPEUTIC TARGETS 2014 MAY; 18(5):513-525
Introduction: Psoriasis is a chronic inflammatory skin disorder determined by the activation of several immune cells and resident tissue cells. Various cytokines mediate inflammatory signals, including IL-23, which is an important factor involved in the differentiation of T helper (Th17) cells. Areas covered: Increasing evidence suggests that IL-23 is a central cytokine to the pathogenesis of psoriasis. An overview on both experimental and human data will be reported in order to support the hypothesis of a key pathogenic role of IL-23/Th17 axis. Expert opinion: Targeting IL-23 might be a more selective, valid and effective therapeutic approach, which, potentially, may show important advantages in terms of long-term efficacy and safety in the treatment of psoriasis.
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S, Marinelli N, Morse DM, Pearson T, Planer M, Ruchti R, Slaunwhite J, Valls N, Wayne M, Wolf M, Woodard A, Antonelli L, Bylsma B, Durkin LS, Flowers S, Hill C, Hughes R, Kotov K, Ling TY, Puigh D, Rodenburg M, Smith G, Vuosalo C, Winer BL, Wolfe H, Wulsin HW, Berry E, Elmer P, Halyo V, Hebda P, Hegeman J, Hunt A, Jindal P, Koay SA, Lujan P, Marlow D, Medvedeva T, Mooney M, Olsen J, Piroue P, Quan X, Raval A, Saka H, Stickland D, Tully C, Werner JS, Zenz SC, Zuranski A, Brownson E, Lopez A, Mendez H, Vargas JER, Alagoz E, Benedetti D, Bolla G, Bortoletto D, De Mattia M, Everett A, Hu Z, Jones M, Jung K, Kress M, Leonardo N, Pegna DL, Maroussov V, Merkel P, Miller DH, Neumeister N, Radburn-Smith BC, Shipsey I, Silvers D, Svyatkovskiy A, Wang F, Xie W, Xu L, Yoo HD, Zablocki J, Zheng Y, Parashar N, Adair A, Akgun B, Ecklund KM, Geurts FJM, Li W, Michlin B, Padley BP, Redjimi R, Roberts J, Zabel J, Betchart B, Bodek A, Covarelli R, De Barbaro P, Demina R, Eshaq Y, Ferbel T, Garcia-Bellido A, Goldenzweig P, Han J, Harel A, Miner DC, Petrillo G, Vishnevskiy D, Zielinski M, Bhatti A, Ciesielski R, Demortier L, Goulianos K, Lungu G, Malik S, Mesropian C, Arora S, Barker A, Chou JP, Contreras-Campana C, Contreras-Campana E, Duggan D, Ferencek D, Gershtein Y, Gray R, Halkiadakis E, Hidas D, Lath A, Panwalkar S, Park M, Patel R, Rekovic V, Robles J, Salur S, Schnetzer S, Seitz C, Somalwar S, Stone R, Thomas S, Thomassen P, Walker M, Rose K, Spanier S, Yang ZC, York A, Bouhali O, Eusebi R, Flanagan W, Gilmore J, Kamon T, Khotilovich V, Krutelyov V, Montalvo R, Osipenkov I, Pakhotin Y, Perloff A, Roe J, Safonov A, Sakuma T, Suarez I, Tatarinov A, Toback D, Akchurin N, Cowden C, Damgov J, Dragoiu C, Dudero PR, Kovitanggoon K, Kunori S, Lee SW, Libeiro T, Volobouev I, Appelt E, Delannoy AG, Greene S, Gurrola A, Johns W, Maguire C, Mao Y, Melo A, Sharma M, Sheldon P, Snook B, Tuo S, Velkovska J, Arenton MW, Boutle S, Cox B, Francis B, Goodell J, Hirosky R, Ledovskoy A, Lin C, Neu C, Wood J, Gollapinni S, Harr R, Karchin PE, Don CKK, Lamichhane P, Belknap DA, Borrello L, Carlsmith D, Cepeda M, Dasu S, Duric S, Friis E, Grothe M, Hall-Wilton R, Herndon M, Herve A, Klabbers P, Klukas J, Lanaro A, Levine A, Loveless R, Mohapatra A, Ojalvo I, Perry T, Pierro GA, Polese G, Ross I, Sakharov A, Sarangi T, Savin A, Smith WH
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Measurement of four-jet production in proton-proton collisions at root s=7 TeV
PHYSICAL REVIEW D 2014 MAY 28; 89(9):? Article 092010
Measurements of the differential cross sections for the production of exactly four jets in proton-proton collisions are presented as a function of the transverse momentum p(T) and pseudorapidity eta, together with the correlations in azimuthal angle and the p(T) balance among the jets. The data sample was collected in 2010 at a center-of-mass energy of 7 TeV with the CMS detector at the LHC, with an integrated luminosity of 36 pb(-1). The cross section for exactly four jets, with two hard jets of p(T) > 50 GeV each, together with two jets of p(T) > 20 GeV each, within vertical bar eta vertical bar < 4.7 is measured to be sigma = 330 +/- 5(stat.) +/- 45(syst.) nb. It is found that fixed-order matrix element calculations including parton showers describe the measured differential cross sections in some regions of phase space only, and that adding contributions from double parton scattering brings the Monte Carlo predictions closer to the data.
Peng T, Hang HC
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SORTing out cellular proteomes in vivo
NATURE BIOTECHNOLOGY 2014 MAY; 32(5):445-446
McGowan BM, Minnion JS, Murphy KG, Roy D, Stanley SA, Dhillo WS, Gardiner JV, Ghatei MA, Bloom SR
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Relaxin-3 stimulates the neuro-endocrine stress axis via corticotrophin-releasing hormone
JOURNAL OF ENDOCRINOLOGY 2014 MAY; 221(2):337-346
Relaxin-3 is a member of the insulin superfamily. It is expressed in the nucleus incertus of the brainstem, which has projections to the hypothalamus. Relaxin-3 binds with high affinity to RXFP1 and RXFP3. RXFP3 is expressed within the hypothalamic paraventricular nucleus (PVN), an area central to the stress response. The physiological function of relaxin-3 is unknown but previous work suggests a role in appetite control, stimulation of the hypothalamic-pituitary-gonadal axis and stress. Central administration of relaxin-3 induces c-fos expression in the PVN and increases plasma ACTH levels in rats. The aim of this study was to investigate the effect of central administration of human relaxin-3 (H3) on the hypothalamic-pituitary-adrenal (HPA) axis in male rodents in vivo and in vitro. Intracerebroventricular (i.c.v) administration of H3 (5 nmol) significantly increased plasma corticosterone at 30 min following injection compared with vehicle. Intra-PVN administration of H3 (1.8-1620 pmol) significantly increased plasma ACTH at 1620 pmol H3 and corticosterone at 180-1620 pmol H3 at 30 min following injection compared with vehicle. The stress hormone prolactin was also significantly raised at 15 min post-injection compared with vehicle. Treatment of hypothalamic explants with H3 (10-1000 nM) stimulated the release of corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP), but H3 had no effect on the release of ACTH from in vitro pituitary fragments. These results suggest that relaxin-3 may regulate the HPA axis, via hypothalamic CRH and AVP neurons. Relaxin-3 may act as a central signal linking nutritional status, reproductive function and stress.
Diaz LL, Zhang JW, Heerdt PM
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Comparative Pharmacodynamics of Pancuronium, Cisatracurium, and CW002 in Rabbits
JOURNAL OF THE AMERICAN ASSOCIATION FOR LABORATORY ANIMAL SCIENCE 2014 MAY; 53(3):283-289
Pancuronium is a long-duration neuromuscular blocking drug (NMBD) that has been used in anesthetized rabbits at 0.1 mg/kg. However, there are limited data regarding the time course for recovery from this dose either spontaneously or with pharmacologic reversal. Here we defined the potency, onset, and recovery characteristics for the intermediate-duration NMBD cisatracurium and CW002 (a novel cysteine-inactivated molecule) in the rabbit, and test the hypothesis that these drugs may be alternatives to 0.1 mg/kg pancuronium for survival procedures. New Zealand white rabbits anesthetized with isoflurane were studied in a cross-over design. Potencies of cisatracurium and CW002 were defined as the effective dose for 95% depression of evoked muscle twitch (ED95). Responses to 3xED(95) were used to define onset (time to maximal effect), recovery index (RI; time from 25% to 75% recovery of twitch), and duration (time to complete recovery). Responses to all drugs were determined with and without reversal by neostigmine glycopyrrolate or L-cysteine. CW002 was 4-fold more potent than was cisatracurium, but their onset, RI, and duration were similar. Pancuronium had similar onset and RI but longer duration, compared with cisatracurium and CW002. Reversal shortened the recovery index and duration for all 3 drugs. At 3xED(95), cisatracurium and CW002 had the same onset as did standard-dose pancuronium, but durations were shorter and more predictable. In addition, CW002 can be reversed without the potential side effects of cholinergic manipulation. We conclude that cisatracurium and CW002 are viable alternatives to pancuronium for survival studies in rabbits.
Schuch R, Lee HM, Schneider BC, Sauve KL, Law C, Khan BK, Rotolo JA, Horiuchi Y, Couto DE, Raz A, Fischetti VA, Huang DB, Nowinski RC, Wittekind M
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Combination Therapy With Lysin CF-301 and Antibiotic Is Superior to Antibiotic Alone for Treating Methicillin-Resistant Staphylococcus aureus-Induced Murine Bacteremia
JOURNAL OF INFECTIOUS DISEASES 2014 MAY 1; 209(9):1469-1478
Lysins are bacteriophage-derived enzymes that degrade bacterial peptidoglycans. Lysin CF-301 is being developed to treat Staphylococcus aureus because of its potent, specific, and rapid bacteriolytic effects. It also demonstrates activity on drug-resistant strains, has a low resistance profile, eradicates biofilms, and acts synergistically with antibiotics. CF-301 was bacteriolytic against 250 S. aureus strains tested including 120 methicillin-resistant S. aureus (MRSA) isolates. In time-kill studies with 62 strains, CF-301 reduced S. aureus by 3-log(10) within 30 minutes compared to 6-12 hours required by antibiotics. In bacteremia, CF-301 increased survival by reducing blood MRSA 100-fold within 1 hour. Combinations of CF-301 with vancomycin or daptomycin synergized in vitro and increased survival significantly in staphylococcal-induced bacteremia compared to treatment with antibiotics alone (P < .0001). Superiority of CF-301 combinations with antibiotics was confirmed in 26 independent bacteremia studies. Combinations including CF-301 and antibiotics represent an attractive alternative to antibiotic monotherapies currently used to treat S. aureus bacteremia.
Garcia-Santamarina S, Boronat S, Domenech A, Ayte J, Molina H, Hidalgo E
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Monitoring in vivo reversible cysteine oxidation in proteins using ICAT and mass spectrometry
NATURE PROTOCOLS 2014 MAY; 9(5):1131-1145
Reversible thiol oxidation of cysteine residues occurs in many intracellular catalytic and signaling processes. Here we describe an optimized protocol, which can be completed in similar to 5 d, to unambiguously identify specific cysteine residues that are transiently and reversibly oxidized by comparing two complex biological samples obtained from yeast cell cultures at the proteome level. After ` freezing' the in vivo thiol stage of cysteine residues by medium acidification, we first block reduced thiols in extracts with iodoacetamide (IAM), and then we sequentially reduce and label reversible oxidized thiols with the biotin-based heavy or light IAM derivatives, which are known as isotope-coded affinity tag (ICAT) reagents, so that the two samples can be compared at once after combination of the labeled extracts, trypsin digestion, streptavidin-affinity purification of peptides containing oxidized cysteines, and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. For the same protein extracts, before cysteine-containing peptide enrichment, individual relative protein concentrations are obtained by stable-isotope dimethyl labeling.
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Malik S, Mesropian C, Arora S, Barker A, Chou JP, Contreras-Campana C, Contreras-Campana E, Duggan D, Ferencek D, Gershtein Y, Gray R, Halkiadakis E, Hidas D, Lath A, Panwalkar S, Park M, Patel R, Rekovic V, Robles J, Salur S, Schnetzer S, Seitz C, Somalwar S, Stone R, Thomas S, Walker M, Cerizza G, Hollingsworth M, Rose K, Spanier S, Yang ZC, York A, Bouhali O, Eusebi R, Flanagan W, Gilmore J, Kamon T, Khotilovich V, Montalvo R, Osipenkov I, Pakhotin Y, Perloff A, Roe J, Safonov A, Sakuma T, Suarez I, Tatarinov A, Toback D, Akchurin N, Damgov J, Dragoiu C, Dudero PR, Jeong C, Kovitanggoon K, Lee SW, Libeiro T, Volobouev I, Appelt E, Delannoy AG, Greene S, Gurrola A, Johns W, Maguire C, Mao Y, Melo A, Sharma M, Sheldon P, Snook B, Tuo S, Velkovska J, Arenton MW, Boutle S, Cox B, Francis B, Goodell J, Hirosky R, Ledovskoy A, Lin C, Neu C, Wood J, Gollapinni S, Harr R, Karchin PE, Don CKK, Lamichhane P, Sakharov A, Belknap DA, Borrello L, Carlsmith D, Cepeda M, Dasu S, Friis E, Grothe M, Hall-Wilton R, Herndon M, Herve A, Kaadze K, Klabbers P, Klukas J, Lanaro A, Loveless R, Mohapatra A, Mozer MU, Ojalvo I, Pierro GA, Polese G, Ross I, Savin A, Smith WH, Swanson J
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Measurement of the W gamma and Z gamma inclusive cross sections in pp collisions at root s=7 TeV and limits on anomalous triple gauge boson couplings
PHYSICAL REVIEW D 2014 MAY 13; 89(9):? Article 092005
Measurements of W gamma and Z gamma production in proton-proton collisions at root s = 7 TeV are used to extract limits on anomalous triple gauge couplings. The results are based on data recorded by the CMS experiment at the LHC that correspond to an integrated luminosity of 5.0 fb(-1). The cross sections are measured for photon transverse momenta p(T)(gamma) > 15 GeV, and for separations between photons and final-state charged leptons in the pseudorapidity-azimuthal plane of Delta R(l,gamma) > 0.7 in l nu gamma and ll gamma final states, where l refers either to an electron or a muon. A dilepton invariant mass requirement of m(ll) > 50 GeV is imposed for the Z gamma process. No deviations are observed relative to predictions from the standard model, and limits are set on anomalous WW gamma, ZZ gamma, and Z gamma gamma triple gauge couplings.
Wei J, Yuen EY, Liu W, Li X, Zhong P, Karatsoreos IN, McEwen BS, Yan Z
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Estrogen protects against the detrimental effects of repeated stress on glutamatergic transmission and cognition
MOLECULAR PSYCHIATRY 2014 MAY; 19(5):588-598
Converging evidence suggests that females and males show different responses to stress; however, little is known about the mechanism underlying the sexually dimorphic effects of stress. In this study, we found that young female rats exposed to 1 week of repeated restraint stress show no negative effects on temporal order recognition memory (TORM), a cognitive process controlled by the prefrontal cortex (PFC), which was contrary to the impairment in TORM observed in stressed males. Concomitantly, normal glutamatergic transmission and glutamate receptor surface expression in PFC pyramidal neurons were found in repeatedly stressed females, in contrast to the significant reduction seen in stressed males. The detrimental effects of repeated stress on TORM and glutamate receptors were unmasked in stressed females when estrogen receptors were inhibited or knocked down in PFC, and were prevented in stressed males with the administration of estradiol. Blocking aromatase, the enzyme for the biosynthesis of estrogen, revealed the stress-induced glutamatergic deficits and memory impairment in females, and the level of aromatase was significantly higher in the PFC of females than in males. These results suggest that estrogen protects against the detrimental effects of repeated stress on glutamatergic transmission and PFC-dependent cognition, which may underlie the stress resilience of females.
Alexander EL, Gardete S, Bar HY, Wells MT, Tomasz A, Rhee KY
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Intermediate-Type Vancomycin Resistance (VISA) in Genetically-Distinct Staphylococcus aureus Isolates Is Linked to Specific, Reversible Metabolic Alterations
PLOS ONE 2014 MAY 9; 9(5):? Article e97137
Intermediate (VISA-type) vancomycin resistance in Staphylococcus aureus has been associated with a range of physiologic and genetic alterations. Previous work described the emergence of VISA-type resistance in two clonally-distinct series of isolates. In both series (the first belonging to MRSA clone ST8-USA300, and the second to ST5-USA100), resistance was conferred by a single mutation in yvqF (a negative regulator of the vraSR two-component system associated with vancomycin resistance). In the USA300 series, resistance was reversed by a secondary mutation in vraSR. In this study, we combined systems-level metabolomic profiling with statistical modeling techniques to discover specific, reversible metabolic alterations associated with the VISA phenotype.