A search for the heaviest isotopes of fluorine, neon, and sodium was conducted by fragmentation of an intense ^{48}Ca beam at 345 MeV/nucleon with a 20-mm-thick beryllium target and identification ...of isotopes in the large-acceptance separator BigRIPS at the RIKEN Radioactive Isotope Beam Factory. No events were observed for ^{32,33}F, ^{35,36}Ne, and ^{38}Na and only one event for ^{39}Na after extensive running. Comparison with predicted yields excludes the existence of bound states of these unobserved isotopes with high confidence levels. The present work indicates that ^{31}F and ^{34}Ne are the heaviest bound isotopes of fluorine and neon, respectively. The neutron dripline has thus been experimentally confirmed up to neon for the first time since ^{24}O was confirmed to be the dripline nucleus nearly 20 years ago. These data provide new keys to understanding the nuclear stability at extremely neutron-rich conditions.
Abstract
α
-RuCl
3
is a major candidate for the realization of the Kitaev quantum spin liquid, but its zigzag antiferromagnetic order at low temperatures indicates deviations from the Kitaev model. ...We have quantified the spin Hamiltonian of
α
-RuCl
3
by a resonant inelastic x-ray scattering study at the Ru
L
3
absorption edge. In the paramagnetic state, the quasi-elastic intensity of magnetic excitations has a broad maximum around the zone center without any local maxima at the zigzag magnetic Bragg wavevectors. This finding implies that the zigzag order is fragile and readily destabilized by competing ferromagnetic correlations. The classical ground state of the experimentally determined Hamiltonian is actually ferromagnetic. The zigzag state is stabilized by quantum fluctuations, leaving ferromagnetism – along with the Kitaev spin liquid – as energetically proximate metastable states. The three closely competing states and their collective excitations hold the key to the theoretical understanding of the unusual properties of
α
-RuCl
3
in magnetic fields.
Cancer initiation and progression are defined by the behavior of cancer cells per se and the development of tumor tissues, both of which are modulated by crosstalk between cancer cells and the ...surrounding microenvironment. Advances in cancer research have highlighted the significance of constant evolution of the tumor microenvironment, leading to tumor formation, metastasis and refractoriness to therapy. MicroRNAs (miRNAs) are small non-coding RNAs that function as major players of posttranscriptional gene regulation in diverse biological processes. They function as both tumor suppressors and promoters in many aspects of the autonomous behavior of cancer cells. Theoretically, dysfunction in the gene regulatory networks of cancer cells is one of the major driving forces for alterations of ostensibly normal surrounding cells. In this context, the core targets of miRNAs, termed miRNA regulons, are currently being expanded to include various modulators of the tumor microenvironment. Recent advances have highlighted two important roles played by miRNAs in the evolution of tumor microenvironments: miRNAs in tumor cells transform the microenvironment via non-cell-autonomous mechanisms, and miRNAs in neighboring cells stabilize cancer hallmark traits. These observations epitomize the distal and proximal functions of miRNAs in tumor microenvironments, respectively. Such regulation by miRNAs affects tumor angiogenesis, immune invasion and tumor-stromal interactions. This review summarizes recent findings on the mechanisms of miRNA-mediated regulation of tumor microenvironments, with a perspective on the design of therapeutic interventions.
The factor that plays the essential role in hydrogen-related failure has been examined for Inconel 625 and iron by means of tensile testing with interposed unloading and reloading with/without ...hydrogen charging. Aging at 30
°C or annealing at 200
°C was conducted during the unloaded stage in order to diffuse out hydrogen or to anneal out strain-induced defects. Hydrogen thermal desorption analysis was used to evaluate strain-induced defects that act as trapping sites of hydrogen. Fracture strain decreased in the initially hydrogen-charged specimens even though hydrogen was absent at the late stage of straining. Annealing at 200
°C at the unloaded stage almost completely recovered the decrease in fracture strain. Enhancement of strain-induced defects by hydrogen and their involvement in degradation were revealed by means of hydrogen thermal desorption analysis. The results provide direct evidence of the primary role of vacancies rather than hydrogen itself in hydrogen degradation, and agree well with the hydrogen-enhanced strain-induced vacancy model with respect to the mechanism of hydrogen-related failure.
Despite the introduction of plasmapheresis and immunoglobulin therapy, many patients with Guillain-Barré syndrome still have an incomplete recovery. Evidence from pathogenesis studies suggests the ...involvement of complement-mediated peripheral nerve damage. We aimed to investigate the safety and efficacy of eculizumab, a humanised monoclonal antibody against the complement protein C5, in patients with severe Guillain-Barré syndrome.
This study was a 24 week, multicentre, double-blind, placebo-controlled, randomised phase 2 trial done at 13 hospitals in Japan. Eligible patients with Guillain-Barré syndrome were aged 18 years or older and could not walk independently (Guillain-Barré syndrome functional grade 3–5). Patients were randomly assigned (2:1) to receive 4 weeks of intravenous immunoglobulin plus either eculizumab (900 mg) or placebo; randomisation was done via a computer-generated process and web response system with minimisation for functional grade and age. The study had a parallel non-comparative single-arm outcome measure. The primary outcomes were efficacy (the proportion of patients with restored ability to walk independently functional grade ≤2 at week 4) in the eculizumab group and safety in the full analysis set. For the efficacy endpoint, we predefined a response rate threshold of the lower 90% CI boundary exceeding 50%. This trial is registered with ClinicalTrials.gov, number, NCT02493725.
Between Aug 10, 2015, and April 21, 2016, 34 patients were assigned to receive either eculizumab (n=23) or placebo (n=11). At week 4, the proportion of the patients able to walk independently (functional grade ≤2) was 61% (90% CI 42–78; n=14) in the eculizumab group, and 45% (20–73; n=5) in the placebo group. Adverse events occurred in all 34 patients. Three patients had serious adverse events: two in the eculizumab group (anaphylaxis in one patient and intracranial haemorrhage and abscess in another patient) and one in the placebo group (depression). The possibility that anaphylaxis and intracranial abscess were related to eculizumab could not be excluded. No deaths or meningococcal infections occurred.
The primary outcome measure did not reach the predefined response rate. However, because this is a small study without statistical comparison with the placebo group, the efficacy and safety of eculizumab could be investigated in larger, randomised controlled trials.
The Japan Agency for Medical Research and Development, Ministry of Health, Labor and Welfare, and Alexion Pharmaceuticals.
Experimental determinations of bulk band topology in the solid states have been so far restricted to only indirect investigation through the probing of surface states predicted by electronic ...structure calculations. We here present an alternative approach to determine the band topology by means of bulk-sensitive soft x-ray angle-resolved photoemission spectroscopy. We investigate the bulk electronic structures of the series materials, Ce monopnictides (CeP, CeAs, CeSb, and CeBi). By performing a paradigmatic study of the band structures as a function of their spin-orbit coupling, we draw the topological phase diagram and unambiguously reveal the topological phase transition from a trivial to a nontrivial regime in going from CeP to CeBi induced by the band inversion. The underlying mechanism of the phase transition is elucidated in terms of spin-orbit coupling in concert with their semimetallic band structures. Our comprehensive observations provide a new insight into the band topology hidden in the bulk states.
Acute myeloid leukemia (AML) involves a block in terminal differentiation of the myeloid lineage and uncontrolled proliferation of a progenitor state. Using phorbol myristate acetate (PMA), it is ...possible to overcome this block in THP-1 cells (an M5-AML containing the MLL-MLLT3 fusion), resulting in differentiation to an adherent monocytic phenotype. As part of FANTOM4, we used microarrays to identify 23 microRNAs that are regulated by PMA. We identify four PMA-induced microRNAs (mir-155, mir-222, mir-424 and mir-503) that when overexpressed cause cell-cycle arrest and partial differentiation and when used in combination induce additional changes not seen by any individual microRNA. We further characterize these pro-differentiative microRNAs and show that mir-155 and mir-222 induce G2 arrest and apoptosis, respectively. We find mir-424 and mir-503 are derived from a polycistronic precursor mir-424-503 that is under repression by the MLL-MLLT3 leukemogenic fusion. Both of these microRNAs directly target cell-cycle regulators and induce G1 cell-cycle arrest when overexpressed in THP-1. We also find that the pro-differentiative mir-424 and mir-503 downregulate the anti-differentiative mir-9 by targeting a site in its primary transcript. Our study highlights the combinatorial effects of multiple microRNAs within cellular systems.
Background. Pruritus in haemodialysis patients is an intractable disease and substantially impairs their quality of life. Based on the results of our earlier clinical study, we hypothesized that the ...μ-(mu) opioid system is itch-inducible, whereas the κ (kappa) system is itch-suppressive. Methods. The efficacy and safety of nalfurafine hydrochloride (a novel κ-receptor agonist) were prospectively investigated by randomly (1:1:1) administering 5 or 2.5 μg of the drug or a placebo orally for 14 days using a double-blind design in 337 haemodialysis patients with itch that was resistant to currently available treatments, such as antihistamines. Results. The mean decrease in the visual analogue scale (VAS) from baseline, the study's primary endpoint, was significantly larger in the 5-μg nalfurafine hydrochloride group (n = 114) than in the placebo group (n = 111, P = 0.0002, one-sided test at 2.5% significance level). The decrease in the VAS in the 2.5-μg group (n = 112) was also significantly larger than that in the placebo group (P = 0.0001). The incidence of adverse drug reactions (ADRs) was 35.1% in the 5-μg group, 25.0% in the 2.5-μg group and 16.2% in the placebo group. Moderate to severe ADRs were observed in 10 of the 226 patients. The most common ADR was insomnia (sleep disturbance), seen in 24 of the 226 nalfurafine patients. Conclusions. This Phase III, randomized, double-blind, placebo-controlled, parallel-group, prospective study based on VAS evaluations clearly showed that orally taken nalfurafine hydrochloride effectively reduced itches that were otherwise refractory to currently available treatments in maintenance haemodialysis patients, with few significant ADRs. This novel drug was officially approved for clinical use in January 2009 by the Ministry of Health, Labour and Welfare of Japan.
•In-flight particle identification of RI beams developed for BigRIPS separator.•Atomic number Z and mass-to-charge ratio A/Q are deduced by the TOF-Bρ-ΔE.•Precise determinations of Bρ and TOF with ...trajectory reconstruction and slew correction, respectively.•The achieved A/Q resolution is high enough to clearly identify the charge state.•Thorough removal of background events improves the reliability of identification.
We have developed a method for achieving excellent resolving power in in-flight particle identification of radioactive isotope (RI) beams at the BigRIPS fragment separator at the RIKEN Nishina Center RI Beam Factory (RIBF). In the BigRIPS separator, RI beams are identified by their atomic number Z and mass-to-charge ratio A/Q which are deduced from the measurements of time of flight (TOF), magnetic rigidity (Bρ) and energy loss (ΔE), and delivered as tagged RI beams to a variety of experiments including secondary reaction measurements. High A/Q resolution is an essential requirement for this scheme, because the charge state Q of RI beams has to be identified at RIBF energies such as 200–300MeV/nucleon. By precisely determining the Bρ and TOF values, we have achieved relative A/Q resolution as good as 0.034% (root-mean-square value). The achieved A/Q resolution is high enough to clearly identify the charge state Q in the Z versus A/Q particle identification plot, where fully-stripped and hydrogen-like peaks are very closely located. The precise Bρ determination is achieved by refined particle trajectory reconstruction, while a slew correction is performed to precisely determine the TOF value. Furthermore background events are thoroughly removed to improve reliability of the particle identification. In the present paper we present the details of the particle identification scheme in the BigRIPS separator. The isotope separation in the BigRIPS separator is also briefly introduced.
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