Experimental demonstration of novel beam characterization using a polarizable X-band transverse deflection structure.

The PolariX TDS (Polarizable X-Band Transverse Deflection Structure) is an innovative TDS-design operating in the X-band frequency-range. The design gives full control of the streaking plane, which can be tuned in order to characterize the projections of the beam distribution onto arbitrary transverse axes. This novel feature opens up new opportunities for detailed characterization of the electron beam. In this paper we present first measurements of the Polarix TDS at the FLASHForward beamline at DESY, including three-dimensional reconstruction of the charge-density distribution of the bunch and slice emittance measurements in both transverse directions. The experimental results open the path toward novel and more extensive beam characterization in the direction of multi-dimensional-beam-phase-space reconstruction.

Magnetic assessment and modelling of the Aramis undulator beamline.

Within the SwissFEL project at the Paul Scherrer Institute (PSI), the hard X-ray line (Aramis) has been equipped with short-period in-vacuum undulators, known as the U15 series. The undulator design has been developed within the institute itself, while the prototyping and the series production have been implemented through a close collaboration with a Swiss industrial partner, Max Daetwyler AG, and several subcontractors. The magnetic measurement system has been built at PSI, together with all the data analysis tools. The Hall probe has been designed for PSI by the Swiss company SENIS. In this paper the general concepts of both the mechanical and the magnetic properties of the U15 series of undulators are presented. A description of the magnetic measurement equipment is given and the results of the magnetic measurement campaign are reported. Lastly, the data reduction methods and the associated models are presented and their actual implementation in the control system is detailed.

Intrinsic emittance reduction of an electron beam from metal photocathodes.

Electron beams in modern linear accelerators are now becoming limited in brightness by the intrinsic emittance of the photocathode electron source. Therefore it becomes important for large scale facilities such as free electron lasers to reduce this fundamental limit. In this Letter we present measurements of the intrinsic emittance for different laser wavelength (from 261 to 282 nm) and for different photocathode materials such as Mo, Nb, Al, Cu. Values as low as 0.41±0.03 mm·mrad/mm laser spot size (rms) were measured for a copper photocathode illuminated with a 282 nm laser wavelength. The key element for emittance reduction is a uv laser system which allows adjustment of the laser photon energy to match the effective work function of the cathode material and to emit photoelectrons with a lower initial kinetic energy. The quantum efficiency over the explored wavelength range varies by less than a factor of 3.

Laser-photofield emission from needle cathodes for low-emittance electron beams.

Illumination of a ZrC needle with short laser pulses (16 ps, 266 nm) while high voltage pulses (-60 kV, 2 ns, 30 Hz) are applied, produces photo-field emitted electron bunches. The electric field is high and varies rapidly over the needle surface so that quantum efficiency (QE) near the apex can be much higher than for a flat photocathode due to the Schottky effect. Up to 150 pC (2.9 A peak current) have been extracted by photo-field emission from a ZrC needle. The effective emitting area has an estimated radius below 50 microm leading to a theoretical intrinsic emittance below 0.05 mm mrad.

Letters from Mapoon: colonising Aboriginal gender.

Much information on traditional indigenous society in Australian historiography and anthropology stems from the vast store of eyewitness accounts left by missionaries, settlers and government officials. How cautious does one need to be in using such material? After all that it reveals about the moral and legal universe of its writers, can it speak reliably about traditional society? This article traces the production of knowledge about indigenous gender relations at Cape York Peninsula through a lineage of sources from the 1890s to the 1990s and concludes that unless the assumptions embedded in the primary sources are clearly identified, the discourse on Aboriginal womanhood continues to be a colonising project.

[Influence of physical activity upon bone mineralization of school age children of both sexes]. / Influencia de la actividad física en la mineralización ósea de escolares de ambos sexos.

Obtention of an optimal peak bone mass decreases the risk of osteoporosis in adult life. An increase of physical activity favors bone mineralization in adults. However, in teenagers sports that could delay puberty can delay bone mineralization, while sports with a normal caloric intake favor mineralization. The objective of this study was to evaluate the effect of intensity of physical activity and the type of sport, upon bone mineralization before and during puberty. A sample of 144 normal school age children of both sexes aged 7 to 14 years, practicing various degrees of physical activity, was selected. Bone mineral density (BMD) of whole body, spine and hip was measured with a dual photon absorptiometry densitometer and compared with values of normal school children of similar ages. A better adequation of BMD of whole body and spine in school age children with increased physical activity was detected. Prepuberal female gymnasts had decreased BMD of whole body. Puberal school age children with decrease physical activity had diminished BMD. These results led us conclude that physical activity favors bone mineralization in spine and hip, specially during puberty.

Differences in backbone structure between angiotensin II agonists and type I antagonists.

Type I angiotensin II antagonists with O-methyl-L-homoserine [HSer(gamma-OMe)] and delta-methoxy-L-norvaline [Nva(delta-OMe)] at position 8 have been prepared by the solid-phase method, purified by reverse-phase HPLC, and bioassayed in the rat uterus, and their backbone conformational properties were investigated by nuclear Overhauser effect (NOE) spectroscopy. [Sar1,HSer-(gamma-OMe)8]ANGII, [HSer(gamma-OMe)8]ANGII, [Des1,HSer(gamma-OMe)8]ANGII, [Sar1,Nva(delta-OMe)8]-ANGII, and [Des1,Nva(delta-OMe)8]ANGII had, respectively, the following antagonist activities, pA2: 7.6, 7.5, < 6.0, 7.1, and 6.9. Analogs of [Sar1]ANGII with delta-hydroxy-L-norvaline [Nva(delta-OH)], delta-methoxy-L-norvaline [Nva(delta-OMe)], 4'-carboxyphenylalanine [Phe(4'-COOH)], and 4'-(trifluoromethyl)phenylalanine [Phe(4'-CF3)] at position 4 were also prepared by solid phase and bioassayed in the rat uterus. [Sar1,Nva(delta-OH)4]ANGII, [Aib1,Nva(delta-OMe)4]ANGII, [Sar1,DL-Phe(4'-COOH)4]ANGII, and [Sar1,DL-Phe(4'-CF3)4]ANGII had, respectively, agonist activities as follows: 4%, 1.5%, 3%, < 0.1%, and < 0.1%. These data emphasize that replacement of Ile8 in Sarilesin with the higher homologs HSer(gamma-OMe) and Nva(delta-OMe) does not greatly alter the structural requirements necessary for expression of type I antagonist activity, while replacement of the tyrosine hydroxyl in [Sar1]ANGII by the carboxylate or the trifluoromethyl group abolishes activity, suggesting that the tyrosinate pharmacophore cannot be replaced by any negatively charged or electronegative group. Conformational investigation of the ANGII type I antagonists [HSer(gamma-OMe)8]ANGII and [Sar1Nva(delta-OMe)8]ANGII in DMSO by 1D-NOE spectroscopy revealed that the Tyr-Ile-His bend, a conformational property found in ANGII and [Sar1]ANGII (J. Biol. Chem. 1994, 269, 5303) is not present in type I antagonists, providing for the first time an important conformational difference between angiotensin II agonists and type I antagonists.

Receptor interactions of the position 4 side chains of angiotensin II analogues: importance of aromatic ring quadrupole.

A triad of interacting groups (TyrOH-His-O2C) in angiotensin II (ANG II) has been postulated to create the tyrosinate anion pharmacophore (tyanophore) responsible for receptor activation/triggering (Biochim. Biophys. Acta 1991, 1065, 21). In the present study we investigated the effects on bioactivity of substituting the Tyr4 residue in [Sar1]ANG II with other anionic or electronegative amino acids, and with a number of aromatic amino acids lacking a hydroxyl group. [Sar1 Nva(delta-OH)4]ANG II, [Sar1 Nva(delta-OCH3)4]ANG II, [Sar1 Met4]ANG II, [Sar1 Gln4]ANG II, [Sar1 Glu4]ANG II and [Sar1 DL-Alg]ANG II had agonist activities in the rat isolated uterus assay of 4, 3, 19, 10, < 0.1 and < 0.1%, respectively, of that of ANG II. [Sar1 Nal4]ANG II, [Sar1 Pal4]ANG II, [Sar1 DL-Phg(4'-F)4]ANG II, [Sar1 Phe(4'-F)4]ANG II, [Sar1 Phe(F5)4]ANG II and [Sar1 His4]ANG II had agonist activities of 4.5, 7, < 0.1, 0.2, 1 and 0.6%, respectively. All peptides investigated were devoid of measurable antagonist activity except [Sar1 Phe(4'-F)4ANG II (pA2 = 7.7). These findings illustrate that anionic or electronegative aliphatic side chains replacing tyrosinate at position 4 can partially activate the angiotensin receptor. For ANG II analogues containing an aromatic amino acid other than Tyr at position 4, ligand binding and agonist activity are not dependent on the electronegativity or dipole moment of the aromatic ring, or on the ability of the 4' ring substituent to accept a proton.(ABSTRACT TRUNCATED AT 250 WORDS)

Transposition of the imidazole ring substituents of angiotensin mimetics related to Losartan.

A series of analogues related to Losartan in which the imidazole ring substituents were transposed have been prepared. Biological evaluation, both in vitro and in vivo, demonstrated that the orientation of the imidazole ring has a subtle yet significant effect upon the potency of these analogues. This information has provided an insight into the possible mode of receptor binding of Losartan and related compounds.

Novel synthesis of cyclic amide-linked analogues of angiotensins II and III.

Cyclic amide-linked angiotension II (ANGII) analogues have been synthesized by novel strategies, in an attempt to test the ring clustering and the charge relay bioactive conformation recently suggested. These analogues were synthesized by connecting side chain amino and carboxyl groups at positions 1 and 8, 2 and 8, 3 and 8, and 3 and 5, N-terminal amino and C-terminal carboxyl groups at positions 1 and 8, 2 and 8, and 4 and 8, and side chain amino to C-terminal carboxyl group at positions 1 and 8. All these analogues were biologically inactive, except for cyclic [Sar1, Asp3, Lys5]ANGII (analogue 10) which had high contractile activity in the rat uterus assay (30% of ANGII) and [Lys1, Tyr(Me)4, Glu8]ANGII (analogue 7) which had weak antagonist activity (PA2 approximately 6). Precyclic linear peptides synthesized using 2-chlorotrityl chloride resin and N alpha-Fmoc-amino acids with suitable side chain protection were obtained in high yield and purity and were readily cyclized with benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate as coupling reagent. Molecular modeling suggests that the ring structure of the potent analogue can be accommodated in the charge relay conformation proposed for ANGII.

Imidazole based non-peptide angiotensin II receptor antagonists. Investigation of the effect of the orientation of the imidazole ring on biological activity.

Non-peptide angiotensin II receptor antagonists related to losartan (DuP 753, CAS 114798-26-4) were prepared and evaluated for antagonist activity in the rat isolated uterus assay. The synthetic strategy concentrated on changes in the orientation of the imidazole ring relative to the substituents, which were maintained in a similar pattern to that found in losartan. The results indicate that biological activity of such antagonists shows little dependence on the orientation of the imidazole ring, but that the spacing of the substituents of primary importance.

Synthesis and biological activities of angiotensin II, Sarilesin, and Sarmesin analogues containing Aze or Pip at position 7.

Analogues of [Sar1]angiotensin II, Sarilesin (type I antagonist), and Sarmesin (type II antagonist) with L-azetidine-2-carboxylic acid (Aze) and L-pipecolic acid (Pip) at position 7 have been prepared by the solid-phase method, purified by reverse-phase HPLC, and bioassayed in the rat uterus. Analogues of the superagonist [Sar1]ANGII with Aze or Pip at position 7 and sarcosine (Sar) or aminoisobutyric acid (Aib) at position 1 had high intrinsic activity in the rat isolated uterus assay (34-184%). Analogues of Sarilesin ([Sar1,Ile8]ANGII) with Aze or Pip at position 7 and Sar or Aib at position 1 retained high antagonist activity (pA2 = 7.1-8.3). Analogues of Sarmesin ([Sar1,Tyr-(OMe)4]ANGII) with Aze and Pip at position 7 had pA2 values of 7.4 and 6.5, respectively. [Aze7]-ANGII and [Pip7]ANGII had low activities (12% and 1%, respectively), and deletion of Sar at position 1 of Sarmesin analogues abolished binding (or affinity) as judged from pA2 values. Nuclear Overhauser effect (NOE) spectroscopy studies of [Sar1,Aze7]ANGII in DMSO-d6 have indicated a clustering of the three aromatic rings (Tyr, His, Phe) and proximity of Sar C alpha and Arg C delta protons to the Tyr/Phe ring protons. These data emphasize that replacement of Pro with the lower and higher homologs Aze and Pip does not greatly alter the structural requirements necessary for expression of agonist or antagonist activity, when sarcosine occupies position 1, but not when Asp occupies position 1, suggesting that there is an intimate relationship between the N-terminal and penultimate residues of the molecule in the biologically active conformation of the molecule.

Importance of the N-terminal domain of the type I angiotension II antagonist [Sar1,Ile8]ANG II for receptor blockade.

Analogues of the Type I angiotensin (ANG) antagonist, [Sar1,Ile8]ANG II, in which the N-terminal dipeptide was modified were synthesized by the solid phase method and purified by reversed-phase HPLC. Antagonist potencies (pA2) of the peptides were determined on the rat isolated uterus using ANG II as the agonist. Substitution of the Arg residue occupying position 2 of [Sar1,Ile8]ANG II (pA2 8.1) by Gly, Ala, Nle, Phe, Pro or Sar reduced the antagonist potency to pA2 = 7.0, 6.8, 6.7, 6.8, 5.8 and 5.3, respectively. Deletion of the N-terminal Sar residue in these same peptides gave pA2 = 6.8, 5.7, 5.5, 5.9, 6.1 and 7.5, respectively. The characteristically long duration of action of [Sar1,Ile8] was absent for all of these analogues including (des1, Sar2, Ile8]ANG II. These findings demonstrate that the antagonist potencies of Type I angiotensin antagonists for smooth muscle receptors, and also the long duration of action, are dependent on the location of positive charges within the peptide and on the conformation of the molecule in determining favorable electrostatic interactions with the receptor. A model is proposed in which the two positively charged loci on the angiotensin molecule (N-terminus and Arg) interact with two corresponding anionic binding sites on the smooth muscle receptor. The possibility that the prolonged duration of action of [Sar1, Ile8]ANG II results from binding to a different site on the angiotensin receptor from that occupied by ANG II is discussed in relation to the present findings.

Synthesis and biological activities of angiotensin II and Sarmesin analogues containing cyclohexylalanine.

Analogues of angiotensin II with cyclohexylalanine (Cha) at position 4 or 8, and analogues of the competitive (type II) angiotensin antagonist [Sar1,Tyr(Me)4]ANG II (Sarmesin) with Cha at position 8, have been prepared by the solid phase method and purified by reversed-phase HPLC. Analogues of ANG II with Cha at position 8 in which the position 1 residue was substituted with sarcosine (Sar) or amino-isobutyric acid (Aib) or was deleted (Des), were slowly reversing (Type I) antagonists with "pA2" values in the rat isolated uterus assay of approximately 8.5. The additional substitution of Tyr(Me) for Tyr at position 4 of these peptides gave reversible competitive (Type I/II) antagonists with pA2 values of 6.7, 5.8, and less than 5, while substitution of Phe for Tyr gave pA2 values of 7.4, 6.7, and less than 5, respectively. All 19 peptides synthesized in this study had low intrinsic agonist activity in the rat isolated uterus assay except for the type I antagonists [Sar1, Cha8]ANG II (7%), [Aib1, Cha8]ANG II (12%) and [Des1, Cha8]ANG II (20%). These data illustrate that the substitution of Cha at position 8 of ANG II analogues produces potent antagonists; however, Type I antagonists retain significant agonist activity whereas Type I/II antagonists do not. In contrast, substitution of Cha at position 4 in a variety of ANG II analogues resulted in severely diminished biological activity, illustrating that the presence of an aromatic ring quadrupole at position 4 is obligatory for receptor binding and activity.

Angiotensin 'antipeptides': (-)messenger RNA complementary to human angiotensin II (+)messenger RNA encodes an angiotensin receptor antagonist.

(-)mRNA complementary to human angiotensin II (+)mRNA encodes the 'antipeptide' Glu-Gly-Val-Tyr-Val-His-Pro-Val which is structurally related to angiotensin II. Angiotensin II 'antipeptide' (antiANG II) and the desglutamyl heptapeptide (antiANG III) are Type I antagonists which inhibit the contractile action of angiotensin at smooth muscle receptors by binding to a negative modulatory site on the angiotensin receptor which is distinct from the angiotensin binding site. These findings may illustrate that the inhibitory binding site on the angiotensin receptor exists to accomodate a naturally occurring inhibitor(s), which is encoded by the DNA strand complementary to that encoding angiotensin II.

Importance of the N-terminal domain of the type II angiotensin antagonist sarmesin for receptor blockade.

Analogues of the competitive angiotensin antagonist [Sar1,Tyr(ME)4]angiotensin II (sarmesin) with modifications at the N-terminus have been prepared by the solid-phase method and purified by reversed-phase HPLC. Substitution of the Sar1 residue of sarmesin with N,N-dimethyl-Gly, N-ethyl-Gly, aminoisobutyric, (methylamino)isobutyric, aminocaproic, and oxamic acids gave analogues that had the following respective antagonist activities (pA2) in the rat isolated uterus assay: less than 6, 6.9, 5.5, 6.0, less than 6, and 5.3. The additional substitution of Ile for Phe at the C-terminus of the latter four peptides gave pA2 values of 7.1, 5.1, less than 5, and 5. Substitution of the Arg2 residue of sarmesin with Nle or Sar abolished antagonist activity. These data emphasize the stringent and discriminating structural requirements in the N-terminal domain of sarmesin that endow this analogue with its antagonist properties and suggest the presence of defined steric constraints in this region of the molecule during receptor blockade.