Systematic evaluation of fluorination as modification for peptide-based fusion inhibitors against HIV-1 infection

With the emergence of novel viruses, the development of new antivirals is more urgent than ever. A key step in human immunodeficiency virus type 1 (HIV-1) infection is six-helix bundle formation within the envelope protein subunit gp41. Selective disruption of bundle formation by peptides has been shown to be effective; however, these drugs, exemplified by T20, are prone to rapid clearance from the patient. The incorporation of non-natural amino acids is known to improve these pharmacokinetic properties. Here, we evaluate a peptide inhibitor in which a critical Ile residue is replaced by fluorinated analogues. We characterized the influence of the fluorinated analogues on the biophysical properties of the peptide. Furthermore, we show that the fluorinated peptides can block HIV-1 infection of target cells at nanomolar levels. These findings demonstrate that fluorinated amino acids are appropriate tools for the development of novel peptide therapeutics

2,2\u27-Dipyrrolidine as a Precursor to Novel Diazatricyclic Systems

Reaction of newly available 2,2\u27-dipyrrolidine with a variety of biselectrophiles gave selectively either novel diazatricyclic systems having bridgehead nitrogen atoms or the N,N\u27-disubstituted-2,2\u27-dipyrrolidines in good to excellent yields

The Impact of Halogenated Phenylalanine Derivatives on NFGAIL Amyloid Formation

The hexapeptide hIAPP(22-27)(NFGAIL) is known as a crucial amyloid core sequence of the human islet amyloid polypeptide (hIAPP) whose aggregates can be used to better understand the wild-type hIAPP ' s toxicity to beta-cell death. In amyloid research, the role of hydrophobic and aromatic-aromatic interactions as potential driving forces during the aggregation process is controversially discussed not only in case of NFGAIL, but also for amyloidogenic peptides in general. We have used halogenation of the aromatic residue as a strategy to modulate hydrophobic and aromatic-aromatic interactions and prepared a library of NFGAIL variants containing fluorinated and iodinated phenylalanine analogues. We used thioflavin T staining, transmission electron microscopy (TEM) and small-angle X-ray scattering (SAXS) to study the impact of side-chain halogenation on NFGAIL amyloid formation kinetics. Our data revealed a synergy between aggregation behavior and hydrophobicity of the phenylalanine residue. This study introduces systematic fluorination as a toolbox to further investigate the nature of the amyloid self-assembly process

First observation of γ rays emitted from excited states south-east of Sn132: The πg−19/2⊗νf7/2 multiplet of In83132

A. Jungclaus et al. ; 6 págs.; 4 figs. ; Rapid CommunicationsFor the first time, the γ decay of excited states has been observed in a nucleus situated in the quadrant south-east of doubly magic Sn132, a region in which experimental information so far is limited to ground-state properties. Six γ rays with energies of 50, 86, 103, 227, 357, and 602 keV were observed following the β-delayed neutron emission from Cd85133, populated in the projectile fission of a U238 beam at the Radioactive Isotope Beam Factory at RIKEN within the EURICA project. The new experimental information is compared to the results of a modern realistic shell-model calculation, the first one in this region very far from stability, focusing in particular on the π0g9/2-1 - ν1f7/2 particle-hole multiplet in In83132. In addition, theoretical estimates based on a scaling of the two-body matrix elements for the πh11/2-1 - νg9/2 analog multiplet in Tl127208, one major proton and one major neutron shell above, are presented. ©2016 American Physical SocietyWe thank the staff of the RIKEN Nishina Center accelerator complex for providing stable beams with high intensities to the experiment. We acknowledge the EUROBALL Owners Committee for the loan of germanium detectors and the PreSpec Collaboration for the readout electronics of the cluster detectors. This work was supported by the Spanish Ministerio de Ciencia e Innovación under Contract No. FPA2011-29854-C04 and the Spanish Ministerio de Economía y Competitividad under Contract No. FPA2014-57196-C5- 4-P, the Generalitat Valenciana (Spain) under Grant No. PROMETEO/2010/101, the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. NRF-2012R1A1A1041763), the Priority Centers Research Program in Korea (2009-0093817), OTKA Contract No. K-100835, JSPS KAKENHI (Grant No. 25247045), the European Commission through the Marie Curie Actions call PEOPLE-2011FP7-IEF under Contract No. 300096 and the German BMBF (No. 05P12RDCIA and No. 05P12RDNUP), and Helmholtz International Center for FAIR.Peer Reviewe

β decay of 129Cd and excited states in 129In

J. Taprogge et al.; 11 pags.; 8 figs.; 2 tabs.; PACS number(s): 23.20.Lv, 23.40.−s, 21.60.Cs, 27.60.+j©2015 American Physical Society. The β decay of 129Cd, produced in the relativistic fission of a 238U beam, was experimentally studied at the RIBF facility at the RIKEN Nishina Center. From the γ radiation emitted after the β decays, a level scheme of 129In was established comprising 31 excited states and 69 γ -ray transitions. The experimentally determined level energies are compared to state-of-the-art shell-model calculations. The half-lives of the two β-decaying states in 129Cd were deduced and the β feeding to excited states in 129In were analyzed. It is found that, as in most cases in the Z < 50, N 82 region, both decays are dominated by the ν0g7/2 → π0g9/2 Gamow–Teller transition, although the contribution of first-forbidden transitions cannot be neglected.This work was supported by the Spanish Ministerio de Ciencia e Innovacion under contracts FPA2009-13377-C02 and FPA2011-29854- C04, the Generalitat Valenciana (Spain) under grant PROMETEO/2010/101, the National Research Foundation of Korea (NRF) grant funded by the Korea government (MEST) (No. NRF-2012R1A1A1041763), the Priority Centers Research Program in Korea (2009-0093817), OTKA contract number K-100835, JSPS KAKENHI (Grant No. 25247045), the European Commission through the Marie Curie Actions call FP7-PEOPLE-2011-IEF under Contract No. 300096, the US Department of Energy, Office of Nuclear Physics, under Contract No. DE-AC02-06CH11357, the “RIKEN foreign research program,” and the German BMBF (No. 05P12RDCIA and 05P12RDNUP) and HIC for FAIR.Peer Reviewe

Age-related decline of peripheral visual processing: the role of eye movements

Earlier work suggests that the area of space from which useful visual information can be extracted (useful field of view, UFoV) shrinks in old age. We investigated whether this shrinkage, documented previously with a visual search task, extends to a bimanual tracking task. Young and elderly subjects executed two concurrent tracking tasks with their right and left arms. The separation between tracking displays varied from 3 to 35 cm. Subjects were asked to fixate straight ahead (condition FIX) or were free to move their eyes (condition FREE). Eye position was registered. In FREE, young subjects tracked equally well at all display separations. Elderly subjects produced higher tracking errors, and the difference between age groups increased with display separation. Eye movements were comparable across age groups. In FIX, elderly and young subjects tracked less well at large display separations. Seniors again produced higher tracking errors in FIX, but the difference between age groups did not increase reliably with display separation. However, older subjects produced a substantial number of illicit saccades, and when the effect of those saccades was factored out, the difference between young and older subjects’ tracking did increase significantly with display separation in FIX. We conclude that the age-related shrinkage of UFoV, previously documented with a visual search task, is observable with a manual tracking task as well. Older subjects seem to partly compensate their deficit by illicit saccades. Since the deficit is similar in both conditions, it may be located downstream from the convergence of retinal and oculomotor signals

The Impact of Halogenated Phenylalanine Derivatives on NFGAIL Amyloid Formation

The hexapeptide hIAPP22–27 (NFGAIL) is known as a crucial amyloid core sequence of the human islet amyloid polypeptide (hIAPP) whose aggregates can be used to better understand the wild-type hIAPP’s toxicity to β-cell death. In amyloid research, the role of hydrophobic and aromatic-aromatic interactions as potential driving forces during the aggregation process is controversially discussed not only in case of NFGAIL, but also for amyloidogenic peptides in general. We have used halogenation of the aromatic residue as a strategy to modulate hydrophobic and aromatic-aromatic interactions and prepared a library of NFGAIL variants containing fluorinated and iodinated phenylalanine analogues. We used thioflavin T staining, transmission electron microscopy (TEM) and smallangle X-ray scattering (SAXS) to study the impact of side-chain halogenation on NFGAIL amyloid formation kinetics. Our data revealed a synergy between aggregation behavior and hydrophobicity of the phenylalanine residue. This study introduces systematic fluorination as a toolbox to further investigate the nature of the amyloid self-assembly process

Study of ground and excited state decays in N approximate to Z Ag nuclei

4 pags., 4 figs. -- CGS15 – Capture Gamma-Ray Spectroscopy and Related TopicsA decay spectroscopy experiment was performed within the EURICA campaign at RIKEN in 2012. It aimed at the isomer and particle spectroscopy of excited states and ground states in the mass region below the doubly magic 100Sn. The N = Z nuclei 98In, 96Cd and 94Ag were of particular interest for the present study. Preliminary results on the neutron deficient nuclei 93Ag and 94Ag are presented. In 94Ag a more precise value for the half-life of the ground state’s superallowed Fermi transition was deduced. In addition the energy spectra of the mentioned decay could be reproduced through precise Geant4 simulations of the used active stopper SIMBA. This will enable us to extract Qβ values from the measured data. The decay of 93Ag is discussed based on the observed implantation-decay correlation events.This work was carried out at the RIBF operated by RIKEN Nishina Center, RIKEN and CNS, University of Tokyo. We acknowledge the EUROBALL Owners Committee for the loan of germanium detectors and the PreSpec Collaboration for the readout electronics of the cluster detectors. This work was supported by the German BMBF under Contract No. 05P12PKFNE and by the U.S. Department of Energy under grant No. DE-FG02-91ER-40609

Slower Visuomotor Corrections with Unchanged Latency are Consistent with Optimal Adaptation to Increased Endogenous Noise in the Elderly

We analyzed age-related changes in motor response in a visuomotor compensatory tracking task. Subjects used a manipulandum to attempt to keep a displayed cursor at the center of a screen despite random perturbations to its location. Cross-correlation analysis of the perturbation and the subject response showed no age-related increase in latency until the onset of response to the perturbation, but substantial slowing of the response itself. Results are consistent with age-related deterioration in the ratio of signal to noise in visuomotor response. The task is such that it is tractable to use Bayesian and quadratic optimality assumptions to construct a model for behavior. This model assumes that behavior resembles an optimal controller subject to noise, and parametrizes response in terms of latency, willingness to expend effort, noise intensity, and noise bandwidth. The model is consistent with the data for all young (n = 12, age 20–30) and most elderly (n = 12, age 65–92) subjects. The model reproduces the latency result from the cross-correlation method. When presented with increased noise, the computational model reproduces the experimentally observed age-related slowing and the observed lack of increased latency. The model provides a precise way to quantitatively formulate the long-standing hypothesis that age-related slowing is an adaptation to increased noise