Micelles by self-assembling peptide-conjugate amphiphile: synthesis and structural characterization.

The solid-phase synthesis of a novel amphiphilic peptide conjugate I, contg. in the same mol. three different functions: N,N-bis[2-[bis(carboxyethyl)amino]ethyl]-L-glutamic acid chelating agent, the CCK8 bioactive peptide, and a hydrophobic moiety contg. four alkyl chains with 18 carbon atoms each, is reported. In water soln. at pH 7.4, I self-assembles in very stable micelles at very low concn. [crit. micellar concn. (cmc) values of 5 10-7 mol kg-1] as confirmed by fluorescence spectroscopy. The structural characterization, obtained with small-angle neutron scattering (SANS) measurements, indicates that the aggregates are substantially represented by ellipsoidal micelles with an aggregation no. of 39 2 and the two micellar axes of about 52 and 26

A new ⁶⁸Ga-labeled somatostatin analog containing two iodo-amino acids for dual somatostatin receptor subtype 2 and 5 targeting.

Somatostatin receptor (SST) targeting, specifically of the subtype 2 (SST2), with radiolabeled somatostatin analogs, is established for imaging and treatment of neuroendocrine tumors. Owing to the concomitant and heterogeneous expression of several subtypes on the same tumor, analogs targeting more subtypes than SST2 potentially target a broader spectrum of tumors and/or increase the uptake of a given tumor. The analog ST8950 ((4-amino-3-iodo)-D-Phe-c[Cys-(3-iodo)-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH <sub>2</sub> ), bearing 2 iodo-amino acids, exhibits sub-nanomolar affinity to SST2 and SST5. We report herein the development and preclinical evaluation of DOTA-ST8950 labeled with <sup>68</sup> Ga, for imaging SST2- and SST5-expressing tumors. Comparative in vitro and in vivo studies were performed with the de-iodinated DOTA-ST8951 ((4-amino)-D-Phe-c[Cys-Tyr-D-Trp-Lys-Val-Cys]-Thr-NH <sub>2</sub> ) and with the reference compounds DOTA-TATE (SST2 selective) and DOTA-NOC (for SST2 and SST5). Compared with <sup>nat</sup> Ga-DOTA-NOC, <sup>nat</sup> Ga-DOTA-ST8950 exhibited higher affinity to SST2 and SST5 (IC <sub>50</sub> (95%CI), nM = 0.32 (0.20-0.50) and 1.9 (1.1-3.1) vs 0.70 (0.50-0.96) and 3.4 (1.8-6.2), respectively), while <sup>nat</sup> Ga-DOTA-ST8951 lost affinity for both subtypes. <sup>nat</sup> Ga-DOTA-ST8950 had the same potency for inducing SST2-mediated cAMP accumulation as <sup>nat</sup> Ga-DOTA-TATE and slightly better than <sup>nat</sup> Ga-DOTA-NOC (EC <sub>50</sub> , nM = 0.46 (0.23-0.92) vs 0.47 (0.15-1.5) vs 0.59 (0.18-1.9), respectively). [ <sup>67</sup> Ga]Ga-DOTA-ST8950 had a similar internalization rate as [ <sup>67</sup> Ga]Ga-DOTA-NOC in SST2-expressing cells (12.4 ± 1.6% vs 16.6 ± 2.2%, at 4 h, p = 0.0586). In vivo, [ <sup>68</sup> Ga]Ga-DOTA-ST8950 showed high and specific accumulation in SST2- and SST5-expressing tumors, comparable with [ <sup>68</sup> Ga]Ga-DOTA-NOC (26 ± 8 vs 30 ± 8 %IA/g, p = 0.4630 for SST2 and 15 ± 6 vs 12 ± 5 %IA/g, p = 0.3282, for SST5, 1 h p.i.) and accumulation in the SST-positive tissues, the kidneys and the liver. PET/CT images of [ <sup>68</sup> Ga]Ga-DOTA-ST8950, performed in a dual HEK-SST2 and HEK-SST5 tumor xenografted model, clearly visualized both tumors and illustrated high tumor-to-background contrast. [ <sup>68</sup> Ga]Ga-DOTA-ST8950 reveals its potential for PET imaging SST2- and SST5-expressing tumors. It compares favorably with the clinically used [ <sup>68</sup> Ga]Ga-DOTA-NOC in terms of tumor uptake; however, its uptake in the liver remains a challenge for clinical translation. In addition, this study reveals the essential role of the iodo-substitutions in positions 1 and 3 of [ <sup>68</sup> Ga]Ga-DOTA-ST8950 for maintaining affinity to SST2 and SST5, as the de-iodinated [ <sup>68</sup> Ga]Ga-DOTA-ST8951 lost affinity for both receptor subtypes

Carers' perceptions of harm and the protective measures taken to safeguard children's health against inhalation of volcanic ash: A comparative study across Indonesia, Japan and Mexico

Volcanic ash contains potentially toxic elements which could affect human health. There is a paucity of research focusing on the impact of airborne volcanic emissions on the health of children, and on their exposure reduction. Children's carers (parents/guardians) are critical to their protection, so documenting their perceptions of the health risk and their knowledge of how to reduce their children's exposure is an important first step to increase our understanding of how risks are acted upon. This article reports the findings of a survey of 411 residents with caring responsibilities for children aged 12 and under in communities near the active volcanoes of Sakurajima in Japan, Merapi in Indonesia, and Popocatépetl in Mexico. Informed by the Protective Action Decision Model (PADM) and Protection Motivation Theory (PMT), we investigated their perceptions of the health effects and harmful consequences of the ash on their children, how important they thought it was to protect them, and the protective actions taken. The Indonesian carers were the most concerned and motivated to protect their children, although, in all three countries, the large majority of carers had adopted protective measures that they perceived to be most effective, such as keeping windows and doors closed. Path analysis illustrated how the connection between perceptions of harm/worry and importance of protection could partially account for higher motivation levels to protect children, in the Indonesian carers. We discuss the key messages conveyed through the findings that are of relevance for policy, practice and training in all three countries

Testing general relativity using golden black-hole binaries

The coalescences of stellar-mass black-hole binaries through their inspiral, merger, and ringdown are among the most promising sources for ground-based gravitational-wave (GW) detectors. If a GW signal is observed with sufficient signal-to-noise ratio, the masses and spins of the black holes can be estimated from just the inspiral part of the signal. Using these estimates of the initial parameters of the binary, the mass and spin of the final black hole can be uniquely predicted making use of general-relativistic numerical simulations. In addition, the mass and spin of the final black hole can be independently estimated from the merger--ringdown part of the signal. If the binary black hole dynamics is correctly described by general relativity (GR), these independent estimates have to be consistent with each other. We present a Bayesian implementation of such a test of general relativity, which allows us to combine the constraints from multiple observations. Using kludge modified GR waveforms, we demonstrate that this test can detect sufficiently large deviations from GR, and outline the expected constraints from upcoming GW observations using the second-generation of ground-based GW detectors.Comment: 5 pages, 2 fig

Pre-clinical evaluation of eight DOTA coupled gastrin-releasing peptide receptor (GRP-R) ligands for in vivo targeting of receptor-expressing tumors

Background: Overexpression of the gastrin-releasing peptide receptor (GRP-R) has been documented in several human neoplasms such as breast, prostate, and ovarian cancer. There is growing interest in developing radiolabeled peptide-based ligands toward these receptors for the purpose of in vivo imaging and radionuclide therapy of GRP-R-overexpressing tumors. A number of different peptide sequences, isotopes, and labeling methods have been proposed for this purpose. The aim of this work is to perform a direct side-by-side comparison of different GRP-R binding peptides utilizing a single labeling strategy to identify the most suitable peptide sequence. Methods: Solid-phase synthesis of eight derivatives (BN1-8) designed based on literature analysis was carried out. Peptides were coupled to the DOTA chelator through a PEG4 spacer at the N-terminus. Derivatives were characterized for serum stability, binding affinity on PC-3 human prostate cancer cells, biodistribution in tumor-bearing mice, and gamma camera imaging at 1, 6, and 24 h after injection. Results: Serum stability was quite variable among the different compounds with half-lives ranging from 16 to 400 min at 37 °C. All compounds tested showed Kd values in the nanomolar range with the exception of BN3 that showed no binding. Biodistribution and imaging studies carried out for compounds BN1, BN4, BN7, and BN8 showed targeting of the GRP-R-positive tumors and the pancreas. The BN8 compound (DOTA-PEG-DPhe-Gln-Trp-Ala-Val-NMeGly-His-Sta-Leu-NH2) showed high affinity, the longest serum stability, and the highest target-to-background ratios in biodistribution and imaging experiments among the compounds tested. Conclusions: Our results indicate that the NMeGly for Gly substitution and the Sta-Leu substitution at the C-terminus confer high serum stability while maintaining high receptor affinity, resulting in biodistribution properties that outperform those of the other peptides

Tenderbake - A Solution to Dynamic Repeated Consensus for Blockchains

First-generation blockchains provide probabilistic finality: a block can be revoked, albeit the probability decreases as the block "sinks" deeper into the chain. Recent proposals revisited committee-based BFT consensus to provide deterministic finality: as soon as a block is validated, it is never revoked. A distinguishing characteristic of these second-generation blockchains over classical BFT protocols is that committees change over time as the participation and the blockchain state evolve. In this paper, we push forward in this direction by proposing a formalization of the Dynamic Repeated Consensus problem and by providing generic procedures to solve it in the context of blockchains. Our approach is modular in that one can plug in different synchronizers and single-shot consensus. To offer a complete solution, we provide a concrete instantiation, called {{Tenderbake}}, and present a blockchain synchronizer and a single-shot consensus algorithm, working in a Byzantine and partially synchronous system model with eventually synchronous clocks. In contrast to recent proposals, our methodology is driven by the need to bound the message buffers. This is essential in preventing spamming and run-time memory errors. Moreover, {{Tenderbake}} processes can synchronize with each other without exchanging messages, leveraging instead the information stored in the blockchain

Inference of the cosmological parameters from gravitational waves: application to second generation interferometers

The advanced world-wide network of gravitational waves (GW) observatories is scheduled to begin operations within the current decade. Thanks to their improved sensitivity, they promise to yield a number of detections and thus to open a new observational windows for astronomy and astrophysics. Among the scientific goals that should be achieved, there is the independent measurement of the value of the cosmological parameters, hence an independent test of the current cosmological paradigm. Due to the importance of such task, a number of studies have evaluated the capabilities of GW telescopes in this respect. However, since GW do not yield information about the source redshift, different groups have made different assumptions regarding the means through which the GW redshift can be obtained. These different assumptions imply also different methodologies to solve this inference problem. This work presents a formalism based on Bayesian inference developed to facilitate the inclusion of all assumptions and prior information about a GW source within a single data analysis framework. This approach guarantees the minimisation of information loss and the possibility of including naturally event-specific knowledge (such as the sky position for a Gamma Ray Burst - GW coincident observation) in the analysis. The workings of the method are applied to a specific example, loosely designed along the lines of the method proposed by Schutz in 1986, in which one uses information from wide-field galaxy surveys as prior information for the location of a GW source. I show that combining the results from few tens of observations from a network of advanced interferometers will constrain the Hubble constant $H_0$ to an accuracy of $\sim 4 - 5$% at 95% confidence.Comment: 13 pages, 25 figures. Accepted for publication in Phys. Rev.

Triple Michelson Interferometer for a Third-Generation Gravitational Wave Detector

The upcoming European design study `Einstein gravitational-wave Telescope' represents the first step towards a substantial, international effort for the design of a third-generation interferometric gravitational wave detector. It is generally believed that third-generation instruments might not be installed into existing infrastructures but will provoke a new search for optimal detector sites. Consequently, the detector design could be subject to fewer constraints than the on-going design of the second generation instruments. In particular, it will be prudent to investigate alternatives to the traditional L-shaped Michelson interferometer. In this article, we review an old proposal to use three Michelson interferometers in a triangular configuration. We use this example of a triple Michelson interferometer to clarify the terminology and will put this idea into the context of more recent research on interferometer technologies. Furthermore the benefits of a triangular detector will be used to motivate this design as a good starting point for a more detailed research effort towards a third-generation gravitational wave detector.Comment: Minor corrections to the main text and two additional appendices. 14 pages, 6 figure

EBP1 and DRBP76/NF90 binding proteins are included in the major histocompatibility complex class II RNA operon

Major histocompatibility complex class II mRNAs encode heterodimeric proteins involved in the presentation of exogenous antigens during an immune response. Their 3′UTRs bind a protein complex in which we identified two factors: EBP1, an ErbB3 receptor-binding protein and DRBP76, a double-stranded RNA binding nuclear protein, also known as nuclear factor 90 (NF90). Both are well-characterized regulatory factors of several mRNA molecules processing. Using either EBP1 or DRBP76/NF90-specific knockdown experiments, we established that the two proteins play a role in regulating the expression of HLA-DRA, HLA-DRB1 and HLA-DQA1 mRNAs levels. Our study represents the first indication of the existence of a functional unit that includes different transcripts involved in the adaptive immune response. We propose that the concept of ‘RNA operon’ may be suitable for our system in which MHCII mRNAs are modulated via interaction of their 3′UTR with same proteins