Design, Synthesis, and Structure−Activity Relationship Exploration of 1-Substituted 4-Aroyl-3-hydroxy-5-phenyl-1H-pyrrol-2(5H)-one Analogues as Inhibitors of the Annexin A2−S100A10 Protein Interaction

This research was supported by grants from Cancer Research UK. H.K.M. was funded by a Biotechnology and Biological Sciences Research Council studentship.S100 proteins are small adaptors that regulate the activity of partner proteins by virtue of direct protein interactions. Here, we describe the first small molecule blockers of the interaction between S100A10 and annexin A2. Molecular docking yielded candidate blockers that were screened for competition of the binding of an annexin A2 peptide to S100A10. Several inhibitory clusters were identified with some containing compounds with potency in the lower micromolar range. We chose 3-hydroxy-1-(2-hydroxypropyl)-5-(4-isopropylphenyl)-4-(4-methylbenzoyl)-1H-pyrrol-2(5H)-one (1a) as a starting point for structure-activity studies. These confirmed the hypothetical binding mode from the virtual screen for this series of molecules. Selected compounds disrupted the physiological complex of annexin A2 and S100A10, both in a broken cell preparation and inside MDA-MB-231 breast cancer cells. Thus, this class of compounds has promising properties as inhibitors of the interaction between annexin A2 and S100A10 and may help to elucidate the cellular function of this protein interaction.Peer reviewe

Update of the Search for the Neutrinoless Decay τ→μγ\tau\to \mu\gamma

We present an update of the search for the lepton family number violating decay $\tau \to \mu\gamma$ using a complete CLEO II data sample of 12.6 million $\tau^+\tau^-$ pairs. No evidence of a signal has been found and the corresponding upper limit is \BR(\tau \to \mu\gamma) < 1.0 \times 10^{-6} at 90% CL, significantly smaller than previous limits. All quoted results are preliminary.Comment: 9 pages postscript, also available through http://w4.lns.cornell.edu/public/CLN

A giant radio flare from Cygnus X-3 with associated Gamma-ray emission

With frequent flaring activity of its relativistic jets, Cygnus X-3 is one of the most active microquasars and is the only Galactic black hole candidate with confirmed high energy Gamma-ray emission, thanks to detections by Fermi/LAT and AGILE. In 2011, Cygnus X-3 was observed to transit to a soft X-ray state, which is known to be associated with high-energy Gamma-ray emission. We present the results of a multi-wavelength campaign covering a quenched state, when radio emission from Cygnus X-3 is at its weakest and the X-ray spectrum is very soft. A giant (~ 20 Jy) optically thin radio flare marks the end of the quenched state, accompanied by rising non-thermal hard X-rays. Fermi/LAT observations (E >100 MeV) reveal renewed Gamma-ray activity associated with this giant radio flare, suggesting a common origin for all non-thermal components. In addition, current observations unambiguously show that the Gamma-ray emission is not exclusively related to the rare giant radio flares. A 3-week period of Gamma-ray emission is also detected when Cygnus X-3 was weakly flaring in radio, right before transition to the radio quenched state. No Gamma rays are observed during the ~ one-month long quenched state, when the radio flux is weakest. Our results suggest transitions into and out of the ultrasoft X-ray (radio quenched) state trigger Gamma-ray emission, implying a connection to the accretion process, and also that the Gamma-ray activity is related to the level of radio flux (and possibly shock formation), strengthening the connection to the relativistic jets.Comment: Accepted for publication in MNRAS. 10 pages 5 figures, 1 tabl

Extended Sentinel Monitoring of Helicoverpa zea Resistance to Cry and Vip3Aa Toxins in Bt Sweet Corn: Assessing Changes in Phenotypic and Allele Frequencies of Resistance

Transgenic corn and cotton that produce Cry and Vip3Aa toxins derived from Bacillus thuringiensis (Bt) are widely planted in the United States to control lepidopteran pests. The sustainability of these Bt crops is threatened because the corn earworm/bollworm, Helicoverpa zea (Boddie), is evolving a resistance to these toxins. Using Bt sweet corn as a sentinel plant to monitor the evolution of resistance, collaborators established 146 trials in twenty-five states and five Canadian provinces during 2020–2022. The study evaluated overall changes in the phenotypic frequency of resistance (the ratio of larval densities in Bt ears relative to densities in non-Bt ears) in H. zea populations and the range of resistance allele frequencies for Cry1Ab and Vip3Aa. The results revealed a widespread resistance to Cry1Ab, Cry2Ab2, and Cry1A.105 Cry toxins, with higher numbers of larvae surviving in Bt ears than in non-Bt ears at many trial locations. Depending on assumptions about the inheritance of resistance, allele frequencies for Cry1Ab ranged from 0.465 (dominant resistance) to 0.995 (recessive resistance). Although Vip3Aa provided high control efficacy against H. zea, the results show a notable increase in ear damage and a number of surviving older larvae, particularly at southern locations. Assuming recessive resistance, the estimated resistance allele frequencies for Vip3Aa ranged from 0.115 in the Gulf states to 0.032 at more northern locations. These findings indicate that better resistance management practices are urgently needed to sustain efficacy the of corn and cotton that produce Vip3Aa

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Observations of 54 Active Galactic Nuclei with the HEGRA System of Cherenkov Telescopes

A sample of 54 selected Active Galactic Nuclei (AGN) has been observed with the HEGRA stereoscopic system of Cherenkov Telescopes between 1996 and 2002 in the TeV energy regime. The observations were motivated by the positive results obtained for Mkn 421 and Mkn 501. The distances of the selected objects vary over a large range of redshifts between z = 0.004 and z = 0.7. Among the observed AGN are the meanwhile established TeV-emitting BL Lac type objects H1426+428 and 1ES1959+650. Furthermore the BL Lac object 1ES2344+514 and the radio galaxy M87 show evidence for a signal on a 4 sigma level. The observation of 1ES2344+514 together with the Whipple results firmly establishes this AGN as a TeV source. Several objects (PKS2155-304, BL Lacertae, 3C066A) that have been claimed as TeV gamma-ray emitters by other groups are included in this data sample but could not be confirmed using data analysed here. The upper limits of several AGN included in this analysis are compared with predictions in the frame-work of SSC models.Comment: 9 pages, 2 figures, 7 tables, submitted to A&

The Peripheral Binding of 14-3-3γ to Membranes Involves Isoform-Specific Histidine Residues

Mammalian 14-3-3 protein scaffolds include seven conserved isoforms that bind numerous phosphorylated protein partners and regulate many cellular processes. Some 14-3-3-isoforms, notably γ, have elevated affinity for membranes, which might contribute to modulate the subcellular localization of the partners and substantiate the importance of investigating molecular mechanisms of membrane interaction. By applying surface plasmon resonance we here show that the binding to phospholipid bilayers is stimulated when 14-3-3γ is complexed with its partner, a peptide corresponding to the Ser19-phosphorylated N-terminal region of tyrosine hydroxylase. Moreover, membrane interaction is dependent on salts of kosmotropic ions, which also stabilize 14-3-3γ. Electrostatic analysis of available crystal structures of γ and of the non-membrane-binding ζ-isoform, complemented with molecular dynamics simulations, indicate that the electrostatic potential distribution of phosphopeptide-bound 14-3-3γ is optimal for interaction with the membrane through amphipathic helices at the N-terminal dimerization region. In addition, His158, and especially His195, both specific to 14-3-3γ and located at the convex lateral side, appeared to be pivotal for the ligand induced membrane interaction, as corroborated by site-directed mutagenesis. The participation of these histidine residues might be associated to their increased protonation upon membrane binding. Overall, these results reveal membrane-targeting motifs and give insights on mechanisms that furnish the 14-3-3γ scaffold with the capacity for tuned shuffling from soluble to membrane-bound states.This work was supported by grants from the Norwegian Cancer Society (to ØH), Junta de Andalucía, grant CVI-02483 (to JMSR), The Research Council of Norway (grant 185181 to A.M.), the Western Norway Health Authorities (grant 911618 to A.M.) and The Kristian Gerhard Jebsen Foundation (to AM)

Measurement of the WWγWW\gamma gauge boson couplings in ppˉp\bar{p} Collisions at s=1.8\sqrt{s}=1.8 TeV

The $WW\gamma$ gauge boson couplings were measured using $p\bar{p}\to \ell\nu\gamma+X$ ($\ell=e,\mu$) events at $\sqrt{s}=1.8$ TeV observed with the {D\O} detector at the Fermilab Tevatron Collider. The signal, obtained from the data corresponding to an integrated luminosity of $13.8 {\rm pb}^{-1}$, agrees well with the Standard Model prediction. A fit to the photon transverse energy spectrum yields limits at the 95% confidence level on the CP--conserving anomalous coupling parameters of $-1.6<\Delta\kappa<1.8$ ($\lambda$ = 0) and $-0.6<\lambda<0.6$ ($\Delta\kappa$ = 0).Comment: 16pages (14pages + 2figure pages) Uses ReVTEX Two postscript files for figures will follow immediatel

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP